Fate of antigen-presenting cells after antigen presentation to Helper T cells

Fate of antigen-presenting cells after antigen presentation to Helper T cells

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In many texts, the Antigen-presenting cells (APCs) that initiate helper T cell responses are often "forgotten" after their antigen presentation function is discussed. I have been wondering how the antigens in these cells are destroyed since they are complexed to MHC II protein (not MHC I).

Yes, the macrophages can receive additional signals from already activated helper T cells to destroy the pathogens harboured in their cytosol, but what about B cells and Dendritic cells which lack such abilities?

In Janeway it's being said without further explanation (I will edit and add reference) that B-cells and macrophages "become targets" of cytotoxic T-cells after these killer cells have become activated, have been primed. However, this answers your question only if presentation on MHCII (not I) implies that presentation on MHCI has occurred as well. Only then APCs that present to T helper will be targeted by cytotoxic T cells and die. According to my basic knowledge that is the case with Dendritic cells and Macrophages. According to the explanatory text of your question Macrophages only receive signals to kill pathogens they include. Your inference may be correct that they cannot become target of T-cytotoxic cells. It is beyond your question to ask if Macrophages always do get that signal. If no that puts them into the same category as Dendritic APCs.

Understanding that there exists a signal to survive (destruction of phagocytoses pathogens) leads the way to understanding that there is cell death without killing by Tc cells: cells that present antigens to T helper cells will "apoptotically" die because they have been infected, if not killed by immune cells to prevent the production and shedding of virions. According to my basic knowledge it is coherent that a cell presenting is a cell sentenced to apoptosis. Killing by T cells is killing at an earlier stage only.

However, I found no reference that explicitly confirms that - maybe with very few exceptions - that B cells do present on MHCI, to the contrary I found reference - I promise to add this one link quite soon - that explicitly states that B cells only endocytose debris, "protein" (in the sense of protein vaccination) i.e. isolated antigen, not whole virous. Thus, any antigen they present would be on MHC II, not I, as the antigen is not "endogeneous", not produced by the B cell as it has not become infected. This inference from basic textbook knowledge is supported, in this context, by the fact that B cells, just as T cells - which they are thought of as of one and the same category, the Lymphcytes - should not be killed after presentation (whereas T8, cytotoxic T cells do not present at all) as parallel to killing of T cells they still have their job to do: presentation activates the B cells which start to divide and produce antibody. Consequently, it matters if a B cell not presenting on MHCI, thus not being killed by Tc cells, is sentenced to apoptosis and cell death because it has engulfed the antigen. In my opinion B cells - and I will add any reference to the contrary - not even need, as Macrophages, a signal to survive, as they cope with antigen alone and there is no interference with their regular by viral infection. (However cells hosting active HIV produce protein for viral ends for a long time before they finally die, but this is different.)

To sum up:

  1. Dendritic cells present on MHCII and I, hence killed by Tc cells or dying by apoptosis

  2. Macrophages present on MHII and I, but according to textbook different to Dendritic cells have the option or are programmed to receive a survival signal to consume the pathogens they harbour

  3. B cells present on MHCII and, according to my understanding: maybe, on MHCI, which would put them too in category 1: same fate as Dendritic cells, however basic knowledge coherently applied speaks in favor for B cells regularly not presenting on MHCI, not getting killed by Tc cells and not undergoing apoptosis as not "infected" by whole virus

So my own personal answer on B cells based on basic textbook knowledge and lack of explicit statements to the contrary might be very different from the answer regarding dendritic cells (and macrophages, see explanatory text of your question).

The B cells do not die after presenting to T Helper cells.

T Cells

Thymus- derived lymphocytes (commonly known as T cells) are cells in the adaptive immune system that attack invading pathogens and infected host cells depending on the T cell type activated. There are two major types of T cells: CD8+ and CD4+. CD8+ T lymphocytes are activated into cytotoxic T cells when antigens are presented to them on class I MHC proteins. Meanwhile CD4+ T lymphocytes are activated into helper T cells when antigens are presented on class II MHC proteins. Cytotoxic T cells kill the body’s own cells when infected with a virus or cancer, while helper T cells assist the immune response when the body is attacked by foreign pathogens (such as bacteria). Helper T cells accomplish this by using TH1 cells to recruit phagocytic cells to the pathogen, while TH2 cells aid antibody production by activating B cells.

T cells can be targeted by viruses such as HIV, where infection reduces available T cells in the body. This allows the body to succumb to new pathogens, as the immune system can no longer properly fight the threat.

F3. T cell activation by Antigen Presenting Cells

  • Contributed by Henry Jakubowski
  • Professor (Chemistry) at College of St. Benedict/St. John's University

Antigen presentation by MHC molecules on activated macrophages and dendritic cells is a bit complicated. Class I MHC proteins are found on most human cells. They present peptides (hot dogs) in the grove (buns) of the MHC protein. It turns out that not only are foreign peptides (from virus proteins for example) are presented, but also self peptides. All these peptides are generated by intracellular proteolysis of proteins - self and nonself by a structure in the cell called a proteasome. Sompayrac suggests that the MHC Class 1 proteins are like "billboards [which] advertise a sampling of all the proteins that are being made in a cell". MHC Class 1 molecules present information about proteins made in the cell. They activate CTLs which can kill the altered cell.

Cytotoxic T cells have another protein CD8, which binds to its T cell receptor. The CTL must also have a second nonspecific signaling protein (as mentioned above in the safety deposit box analogy) for cell activation.

Class II MHC proteins are found on immune cells (macrophages, etc) which present antigen to T cells, especially T helper cells. They present information about proteins found outside of the cells (such as on bacteria) but whose proteins might end up inside the antigen presenting cell like a macrophage. They activate T helper cells which, through release of signaling molecules called cytokines, activate other immune cells. B cells, before activation by antigen, express little MHCII proteins (and small amounts of B7). After activation, they express more of these proteins and can activate T helper cells.

T helper cells and CTLs differ in another way. T helper cells have another protein CD4, which binds to its T cell receptor, while CTLs have the protein CD8 bound. Both cells must also have a second nonspecific signaling protein (as mentioned above in the safety deposit box analogy) for cell activation.

Sompayrac asks another interesting question. Why is antigen presentation by MHC proteins necessary at all? B cells don't really need presentation since they can bind antigen with membrane antibody molecules. Why do T cells need it. He gives different reasons for Class I and Class II presentations:

Class I MHC (found on most body cells): T cells need to be able to see what is going on inside the cell. When virally-infected cells bind foreign peptide fragments and present them on the surface, they can be "seen" by the appropriate T cell. It's a way to get a part of the virus, for example, to the surface. They can't hide out in the cell. T cells don't need to recognize extracellular threat since antibodies from B cells can do that. Presentation is also important since viral protein fragments that might be found outside of the cell might bind to the outer surface of a noninfected cell, that would then be targeted for killing by the immune system. That wouldn't be good. It also helps that peptide fragments are presented on the surface. This allows parts of the protein that are buried and not exposed on the surface, which would be hidden from interaction with outside antibodies, to be used in signaling infection of the cell by a virus.

MHC Class II (found on antigen-presenting cells like macrophages): In this way two different cells (the presenting cell and the T helper cell) must interact for a signal for immune system activation to be delivered to the body. Again it is a safety mechanism to prevent nonspecific activation of immune cells. Also, as in the case above, since fragments are presented, more of the foreign "protein" can contribute to the signal to activate the immune system.

Function of Antigen presenting cell (APC)

Antigen presenting cell (APC) is specialized cell of our immune system that can recognize the foreign antigen or pathogenic substances and engulf them by endocytosis and break them down into small peptides and after this whole process they present these peptides (or the parts of the antigen) to other immune cells (mainly the T-lymphocytes) and induces immune response for these extracellular antigen. They present antigen by forming a complex of antigen and MHC molecule which is expressed on the surface of APC. So the main function of antigen presenting cell is antigen processing and presentation.

T-cell maturation by antigen presentation by APC by binding of TCR with Ag-MHC complex.

CELLS THAT SERVE AS APC: Many different cells of our immune system serve as APC, but dendritic cells, macrophages and B-lymphocytes are serve as the principal antigen presenting cells which present antigen mainly to the T-lymphocytes. After the interaction with Ag-MHC complex T-cell become activated and differentiated into mature or effector cells (both helper and cytotoxic T-cell) and triggered the further immune response .

Activation and maturation of T-cell through antigen presentation by macrophage and B-cell (both are APC).

LOCATION OF APC : Generally, antigen presenting cells are located on lymphoid tissue, connective tissues, and in blood circulation. Sometimes some APCs (dendritic cells) are present on skin and mucosal epithelium.

PROPERTIES OF APC: The noticeable characters of APC are

  • These are nucleated cells containing major histocompatibility complex (MHC) on the surface or the plasma membrane. The MHC molecule present on APC are mainly class-II MHC. Which form a complex with the antigenic particles, endocytosed by the APCs and helps to express it on the surface to another cells.
  • These are naturally phagocytic cells according to their function.

ANTIGEN PRESENTATION: The main function of an Antigen presenting cell is antigen presentation.

  • Firstly, antigen presenting cells recognize and engulf the extracellular antigen or pathogenic material through endocytosis and enters it into a vessel containing many types of degradative enzymes, called phagosome. After that the phagosome fuses with cellular lysosome and form phagolysosome, containing degradative lysosomal enzymes. Through this process the breakdown of antigen or pathogen into small peptides is done.
  • These peptide antigen (derived after the degradation of pathogen like virus, bacteria and other microbes) then processed and presented to the immature or naïve Helper T-cell and Cytotoxic T-cell through MHC molecule. It uses different MHC molecule in different antigen presentation pathways.
  • The process of antigen presentation by APC is occur in different pathways -a. cytosolic pathway, and b. endocytic pathway. And they present two types of protein antigens – Exogenous and Endogenous antigens.
  • In Cytosolic Pathway, endogenous antigens are synthesized inside the infected cells and these are presented through class-I MHC molecule. Naïve Cytotoxic T-cells (containing CD8 marker) only can recognize the Ag with Class-I MHC present on the surface of APC. They come and bind to the Ag-MHC-I complex by the receptor (TCR).
  • In Endocytic Pathway, the extracellular antigen which derived from the degradation of extracellular pathogens, are presented to the immature or naïve T-helper cell containing CD4 marker. T-helper cell only can recognize the antigen binding with MHC-II molecule expressed on the surface of the antigen presenting cells. T-helper cell interact with the APC by binding with the Ag-MHC complex through T-cell receptor, and become activated or mature and trigger the further immune response.

Antigen presenting cells are referred as this for their function of antigen processing and presentation.

153 years after discovery of the immune system's dendritic cells, scientists uncover a new subset

Artistic rendering of the surface of a human dendritic cell illustrating sheet-like processes that fold back onto the membrane surface. Credit: National Institutes of Health (NIH)

When pathogens invade or tumor cells emerge, the immune system is alerted by danger signals that summon a key battalion of first responders, the unsung heroes of the immune system—a population of starfish-shaped sentinels called dendritic cells.

Without them, coordination of the immune response would be slower and less-well organized. Yet even in the face of such an indispensable role, it has taken until now to discover how a sub-population of these cells doesn't perish after completing their primary job in the immune system.

Dendritic cells were discovered in 1868, and at that time were misunderstood and wrongly categorized as members of the nervous system. But immunologists now know there are different types of these cells, even though they all look alike and have roughly the same job as sentinels in the immune system –on patrol 24/7, hunting down infiltrating causes of infection and disease. What separates one group from another, scientists in Germany have just found, is their response to certain signaling molecules and how long they survive in tissues and the blood.

First off, the shape is no accident of nature. It allows these cells to perform their primary role, which involves obtaining microscopic samples—antigens—from an infiltrator slated for destruction. Dendritic cells engulf snippets of the invader and literally present those antigens to key warriors of the immune system.

These highly mobile cells travel to sites where disease-killing immune cells reside to present their samples, introducing T cells, for example, to the enemy that awaits. Formally, the activity of presenting the sample to T cells is called antigen presentation. For all the work involved with alerting the body to danger, a major group of dendritic cells is programmed to die after a job well done.

Now, in a groundbreaking series of studies, a large team of researchers from throughout Germany has discovered why a unique population of dendritic cells doesn't die after antigen presentation. The sub-population continues to stimulate parts of the immune system to aid the fight against invasive viruses, bacteria or potentially deadly tumor cells.

The finding is likely to be viewed as welcome news in a world beset by a pandemic virus and a slew of worrisome variants. All have stoked concerns about the longevity of immunity triggered by COVID-19 vaccines. Another major role of dendritic cells, as it turns out, is marshaling immune forces in response to vaccination.

To understand the importance of the new research, it's first necessary to detour away from the new finding to delve instead into a primer on the two divisions of the human immune system: the innate and the adaptive.

Also, to fully grasp the research, it's important for another quick lesson: Dendritic cells 101. The new finding, scientists say, promises to change how the cells are defined going forward.

The innate immune system is composed of the big eaters, the so-called professional phagocytes that devour as much of an invading enemy as possible, chewing them into harmless trash. This part of the immune system also releases a tsunami of cytokines and other inflammatory molecules. Adaptive immunity is anchored by the big daddies of the immune response, mainly the various populations of B and T cells.

Dendritic cells, or DCs as they're also known, are the antigen-presenting population, which simply means they engulf a sample of an invader and race to present it to disease-fighting warriors of the adaptive immune system. But dendritic cells have a greater role: They actually activate the adaptive immune response. As a member of the adaptive immune system, dendritic cells serve as a bridge between the innate and adaptive systems.

Signaling activity initiated by the innate immune system's inflammatory molecules stimulates a swift response by dendritic cells, which are already on patrol—on the hunt for invasive trouble.

Despite the chore of activating key players of the adaptive immune system, namely T cells—and, somewhat indirectly, triggering antibody-producing B cells—armies of DCs are inescapably doomed to death. Once their primary jobs of antigen presentation and stimulating the adaptive response are done, the cells are subject to programmed cell death, apoptosis, which leads to their demise. Simply put, nature ensured that armies of dendritic cells perish once their primary roles are complete. Fresh recruits replace the old cells in a renewal process that begins in the bone marrow.

Drs. Lukas Hatscher and Diana Dudziak of the Laboratory of Dendritic Cell Biology at University Hospital Erlangen, a division of Friedrich-Alexander University, led the team that uncovered a long-lasting subset of dendritic cells. They've identified them as human type 2 conventional dendritic cells.

Hatscher, Dudziak and their collaborators analyzed this dendritic population, obtaining them from a variety of sites—the blood, spleen and thymus. The organ-derived DCs used in the research were acquired from donated organs. Scientists compared their activity to human type 1 conventional dentritic cells. They found that longevity distinguished the type 2 population from the doomed type 1s.

Hiding in Plain Sight

The big surprise in the research was discovering that this elusive group of DCs had been hiding all along in plain sight. The challenge for the German team was elucidating why type 2 DCs stay active even though type 1s are programmed to die.

"Instead, these cells entered a 'hyperactive' state that enhanced the stimulation of certain T helper cell subsets," Hatscher and Dudziak wrote in the journal Science Signaling, describing the dendritic cell population they discovered. "The findings suggest that conventional dendritic cells type 2 could be critical to the efficacy of vaccines and immunotherapies as well as for therapeutically controlling inflammation."

The German team confirmed that type 2 DCs augment immune system activity by responding to inflammasome signaling. Chemically, inflammasomes are complex polymers and part of the innate immune system. Inflammasome signaling induces cytokines. The DC response to inflammasomes also occurs in vaccine immunity and the body's ability to repel infections, Hatscher and Dudziak found.

Type 1 dendritic cells tend to undergo regulated cell death after inflammasomes activate. But the investigators found that automatic death wasn't inevitable for type 2 DCs, which did not succumb after inflammasome activation. Type 2 DCs not only survived, but continued their role as a bridge between the innate and adaptive immune systems. The researchers suggest that these cells may be prime targets for approaches to treat inflammatory diseases or to boost the effects of vaccines and adjuvants.

"When conventional type 2 dendritic cells were stimulated with ligands that weakly activated the inflammasome, the DCs did not enter [programmed cell death], but instead secreted interleukin-12 family of cytokines [IL-12] and interleukin-1β [IL-1β]. These cytokines induced prominent T helper type 1 cells and T helper 17 responses," the scientists wrote.

The discovery of how some dendritic cells survive and others are programmed to die was made by a large team of immunobiologists who represented more than a dozen leading research centers throughout Germany. Investigators described the signaling pathway that alerts these cells, and defined the biological role of dendritic sub-population. Scientists proved in their research that nuances of difference separate type 2 conventional dendritic cells differed from type 1s. "We found that the conventional type 2 dendritic cell subset is the major human DC subset," the researchers concluded.

Dendritic cells, in general, act as sentinels by conducting surveillance in tissues. For instance, they can detect infection in the body by pinpointing "danger signals" linked with invading pathogenic agents. Dendritic cells regardless of type zero in on PAMPS—pathogen-associated molecular patterns—which are derived from microorganisms. One of the most notorious PAMPs is a potentially deadly bacterial component known as lipopolysaccharide, or LPS, which is found on the outer cell wall of gram-negative bacteria. Dendritics obtain antigens from the deadly invasive source—and the launch of the adaptive immune system assault on the infiltrator begins.

While the findings by Hatscher, Dudziak and their colleagues may prompt scientists worldwide to take stock of a broader role for these immune system constituents, it's now clear that Germany has been in the vanguard of dendritic cell research for 153 years.

German pathologist Paul Langerhans, while still a medical student, was the first to describe DCs in skin cells. Although he mistakenly defined them as nerve cells, he is credited with bringing attention to bear on this hardworking cell population. (Langerhans is also famous for research involving the pancreas. An insulin-secreting cluster of cells in the pancreas is named after him: the islets of Langerhans).

Hatscher and Dudziak, meanwhile, report that their 21st-century discovery not only enhances overall knowledge about the immune system, but paves the way for using this new knowledge in the fight against disease processes. "These findings not only define the human conventional type 2 dendritic cell subpopulation as a prime target for the treatment of inflammasome-dependent inflammatory diseases, but may also inform new approaches for adjuvant and vaccine development."

DC instruction of CD4+ T cell differentiation

Instruction of Th1 differentiation

Th1 cells are defined by their production of IFNγ and are associated with protective immunity against intracellular pathogens and viruses. 114 The Th1 transcriptional program is driven by IFNγ, 115,116 IL-12, 117 and IL-27, 118 which promote the upregulation of Tbet and IL-12Rβ in CD4+ T cells. 119 IL-12 signaling reinforces the Th1 program and is essential for optimal Th1 differentiation in both mice and humans. 120,121,122

cDC1 are a major source of IL-12 in vivo. 123,124,125 They constitutively express high levels of Il12b transcripts, with evidence of constitutive IL-12p40 protein production in mice. 126,127 As such, cDC1 are commonly associated with Th1 responses and are often portrayed as the principal Th1-inducing cDC subset. Indeed, cDC1 are more efficient than cDC2 at inducing Th1 differentiation in ex vivo coculture systems, 128 presumably due to their baseline expression of IL-12. Th1 responses are also significantly compromised in some systemic, 129 cutaneous 123,130 and intestinal infection models 129,131,132,133 when cDC1 are absent, suggesting that cDC1 are required to support some protective Th1 responses in vivo. However, there is a notable body of literature implicating moDC in driving Th1 responses during infection with Plasmodium, 134 T. gondii 62 , or Salmonella 135 as well as in CpG- or CFA-based immunization models. 136,137 It is not clear whether moDC can serve as antigen-presenting cells in these settings given their low expression of MHCII and co-stimulatory molecules. 18,138 Although inefficient providers of signals 1 and 2, moDC are a good source of signal 3 and can produce high levels of IL-12p40 in vitro 137,138 and in vivo (Hilligan et al., submitted manuscript). A cooperation between moDC and cDC has been suggested by several studies that designated moDC as regulators of Th1 differentiation and cDC as inducers of Th1 proliferation. 135,136,138,139 Finally, a recent study has demonstrated a role for TNFR2+ cDC2 in driving Th1 responses following intranasal immunization with a mucosal adjuvant. 140 Specific targeting of this cDC population reduced recall Th1 responses in the lung and abrogated immunization specific antibody production. 140 Together, these data suggest that a number of DC subsets have the capacity to support Th1 differentiation in vivo and the context and location of infection or immunization determines the DC subset requirements.

Given the critical requirement for IL-12 in Th1 immune responses, signals that regulate IL-12 expression in DC likely contribute to potentiating Th1 differentiation. Interestingly, constitutive IL-12p40 production by cDC1 is maintained under germ-free and antigen-free conditions, (Kawabe et al., submitted manuscript) suggesting that IL-12 production is intrinsically coupled to the cDC1 lineage and is not the result of exogenous microbial signals. Homeostatic IL-12 is thought to function as a regulator of Th2 responses 126,127 and support the generation of innate-like Tbet hi memory-phenotype (MP) CD4+ T cells (Kawabe et al., submitted manuscript) that can produce IFNγ in the absence of TCR signaling and provide early host protection against infection. 141

During infection or inflammation, a number of signals induce or enhance IL-12 production by DC. Firstly, signaling through PRR such as TLR3 and TLR9 enhances DC expression of IL-12p40, 142,143,144 and the engagement of multiple PRR synergizes to boost IL-12 production. 145 Secondly, CD40:CD40L interactions between DC and T cells promotes transcription of the IL-12p35 subunit in DC, 146,147 supporting the production of bioactive IL-12p70. Finally, IFNγ derived from NK or T cells feedbacks on DC to further promote IL-12 production. 148,149,150 IFNγ also promotes cDC and moDC expression of CXCR3 ligands which recruit CXCR3+ pre-Th1 cells to a niche that favors Th1 differentiation. 4,151,152 DC–NK cell crosstalk likely facilitates the generation of Th1 cells through this pathway. 153 It is possible that the main role of cDC1 in Th1 immunity is their involvement in eliciting early IFNγ from NK 154 and CD4+ MP cells 141 that then conditions cDC2 and moDC towards a Th1-inducing phenotype.

Instruction of Th2 differentiation

Th2 cells produce IL-4, IL-5, and IL-13 155 and are associated with helminth infection, exposure to venoms, and allergic disease. 156 IRF4+ cDC2 are necessary for promoting Th2 differentiation in the skin, 51 lungs, 157 and intestinal tract, 132,158 with KLF4-dependent 37 and CD301b+ PDL2+ cDC2 subsets 49,159 specifically implicated in Th2 models. LC may also support Th2 responses in the skin as LC depletion impairs IL-4 production following epicutaneous application of protein antigen 160 or a vitamin D analog that drives an atopic dermatitis-like phenotype in mice. 161 In contrast, cDC1 negatively regulate Th2 responses through constitutive IL-12p40 production and their absence can increase the levels of Th2 cytokines in mouse models of helminth infection 126,132 and house dust mite allergy. 127 The inhibitory effect of cDC1 appears to vary depending on the Th2 model being used, and in some cases it can also be observed for LC, 162 which also constitutively express some level of Il12b. 9 In this respect it is also important to note that, while lower IL-12 production may result in increased Th2 responses in some models, IL-12-KO mice exposed to Th1 stimuli develop lower Th1 responses without defaulting to Th2. 163 Thus, lack of IL-12 may contribute but is not sufficient for Th2 differentiation.

Exposure to helminth products endows cDC2 with the capacity to induce Th2 differentiation, suggesting that DC instruction of Th2 responses is an active process rather than a default one. 96,158,164,165,166 Indeed, there is evidence that the S. mansoni egg antigen (SEA)-derived protein Omega1 inhibits IL-12 production by DC and alters DC morphology to limit contact time with CD4+ T cells, 167,168 two factors thought to contribute to Th2 differentiation. 169 In an in vitro model, SEA can also trigger Dectin-1 and Dectin-2 receptors on DC, leading to prostaglandin-dependent expression of OX40L and development of Th2 responses. 166 In the same study, in vivo experiments in mice also supported a pro-Th2 role of Dectin-2 in the SEA response.

Transcriptomic analysis of helminth- or allergen-conditioned cDC has identified thymic stromal lymphopoietin (TSLP) and IFN-I as upstream regulators of helminth or allergen-induced transcriptional networks in cDC. 162,170 These signatures are restricted to Ag+ cDC2, with comparatively little change observed in the transcriptional profile of Ag− cDC2 and cDC1 compared with baseline. 4,162 TSLP has long been associated with allergic responses in mice and humans, and is known to be a potent inducer of DC activation accompanied by the upregulation of Tnfsf4 (encoding OX40L), and the expression of the chemokines Ccl17 and Ccl22 to attract CCR4-expressing Th2 cells (reviewed in ref. 171 ). However, it is important to note that the DC-specific effects of TSLP signaling are complicated by the finding that TSLP also acts directly on T cells to promote the secretion of type-2 cytokines. 172,173 A recent OVA allergy model employing Tslpr fl/fl animals crossed to cDC-specific (Zbtb46) or CD4+ T cell-specific (Cd4) Cre lines demonstrates that TSLPR signaling in both cell types is important for driving Th2 inflammation. 174 IFN-I signaling has been more recently associated with Th2 responses, and interestingly, is only associated with Th2 responses in some settings, such as intradermal injection of N. brasiliensis larvae or house dust mites. In these cases, IFNAR signaling is required to promote robust IL-4 production by Th2 cells in vivo. 162,175 The IFN-I requirement for Th2 responses is likely due to a direct effect on DC rather than T cells, as suggested by experiments using immunization with IFNAR-deficient BM-DC. 175 IFNAR blockade does not impact cDC2 activation or migration, 162 suggesting that other IFN-I driven signals within DC support instruction of Th2 responses. Further investigation of IFN-I driven transcriptional programs in DC may uncover previously unidentified signals involved in Th2 differentiation.

In conclusion, the DC-derived signals required to initiate and reinforce the Th2 differentiation program remain currently unclear. A source of IL-4 appears to be required to support IL-4 production by Th2 cells in vivo, 176 a finding that may reflect the recognized role of IL-4 in Th2 differentiation in vitro. 177 However, the origin of this early IL-4 production remains undefined, with no evidence suggesting that DC might be the source of such IL-4. While TSLP and IFN-I can condition DC and promote Th2 development, neither is essential except in rare cases. OX40L–OX40 interactions between DC and CD4+ T cells, as well as the DC-derived chemokines CCL17, CCL22, and possibly CCL8, may support Th2 differentiation 178,179,180,181,182 however, it remains to be determined whether these signals are definitive Th2 polarizers or are merely involved in co-stimulation 183 and Th2 cell trafficking, 184,185 respectively. Future studies may provide new information on this important question.

Instruction of Th17 differentiation

Th17 cells are characterized by production of IL-17 and are required for resolving extracellular bacterial and fungal infections. Th17 cells are also strongly implicated in pathogenesis of many autoimmune diseases, including multiple sclerosis and psoriasis. 186 IL-6 and TGFβ are critical signals for Th17 differentiation in vitro, 186 whereas IL-1β and IL-23 can support Th17 differentiation in vivo in the presence of IL-6 or TGFβ. 187,188

LC have a documented association with cutaneous Th17 responses and accumulate in psoriatic lesions. 189 Studies in mice have shown that LC are a significant source of IL-6 and depletion of LC in the context of an epicutaneous C. albicans infection significantly reduces the number of antigen-specific Th17 cells in the dLN. 130,190 However, other studies have found no role for LC in driving cutaneous Th17 inflammation. 191 Instead, dermal cDC2 have been implicated, 192 which is in line with a large body of data showing that IRF4-dependent cDC2 are required to support Th17 differentiation across a number of tissues including the lung 36,193 and intestine. 38,35,54,194,195,196 Unlike the cDC2 involved in promoting Th2 immune responses, Th17-promoting cDC2 require Notch2, but not KLF4, for their development. 195 Finally, CCR2-dependent moDC have also been associated with promoting Th17 responses in an oropharyngeal candidiasis model. Similar to Th1 models, moDC are thought to cooperate with cDC to facilitate optimal Th17 differentiation. 197

DC provide many of the required Th17 differentiation signals in vivo 192,193,195,198 and facilitate the activation of latent TGFβ via αvβ8 integrin. Indeed, DC-specific deletion of αvβ8 significantly blunts Th17 responses in the lamina propria 199 and limits IL-17-mediated pathology in an experimental autoimmune encephalitis model. 200,201 A number of signaling pathways are involved in inducing IL-6 and IL-23 production by cDC, including signaling via TLR2 and Dectin-1, PRR that recognize glucans enriched in fungal cell walls. 148,190 TLR2 engagement preferentially induces IL-23 over the related cytokine IL-12, 202 suggesting that the distribution of PRR activation directly influences DC expression of Th cell polarization factors. Signaling via other PRR can also promote IL-23 and IL-6 production by DC, including imiquimod engagement of TLR7 in dermal cDC 191 and flagellin activation of TLR5 in lamina propria cDC2. 196 More recently, interactions between stromal cells, neural networks, and DC have been implicated in eliciting and potentiating Th17 immunity, particularly in the skin. Fibroblast-derived prostaglandin E2 (PGE2) can promote IL-23 production by preactivated human cDC, and skin fibroblasts from psoriasis patients were found to express considerable levels of COX-2, an enzyme involved in prostaglandin synthesis. In turn, cDC-derived TNFα and IL-1β promote fibroblast secretion of PGE2, implicating fibroblast-DC cross-talk in potentiating Th17 inflammation. 203 Similarly, calcitonin gene-related peptide (CGRP), a neuropeptide derived from sensory TRPV1+ neurons, promotes IL-23 production by dermal cDC2 following C. albicans infection, or induction of psoriasiform inflammation in mice. 204,205 TRPV+ neurons can also trigger CGRP release at sites adjacent to infection, pre-empting cDC responses to help contain infection. 206

Instruction of iTreg differentiation

In the periphery, CD4+ T cells can differentiate into inducible regulatory Th cells (iTreg) that limit inflammation and establish immunological tolerance. 207 iTreg can be distinguished from the thymus-derived natural Treg, which are not considered in this review, through their expression of the transcription factor Helios, which is expressed by natural Treg but not iTreg. 208 TGFβ and IL-2 signaling are important determinants of iTreg differentiation, 209,210,211 with cDC-dependent activation of TGFβ important for optimal iTreg induction. 212 In addition, cDC expression of BTLA 213 and cDC-derived retinoic acid 214,215 support iTreg differentiation in vivo by negatively regulating molecules associated with the differentiation of other effector CD4+ T cell subsets. 216,217 Treg-DC cross-talk may also play a role in limiting inflammatory responses as Treg actively deplete CD80, CD86, 218,219 and peptide–MHCII complexes from cDC. 220

The involvement of DC in instructing iTreg differentiation has been largely studied in the context of the intestine where DC-derived signals are known to play an important role in inducing immunological tolerance to food proteins. 221 IRF8- and BATF3-dependent cDC1 are necessary for optimal iTreg induction, 129,221 which is in line with their selectively high expression of BTLA, 213 Aldh1a2 (encoding retinaldehyde dehydrogenase 2 or RALDH2), an enzyme involved in retinoic acid production, Tgfb2, and Itgb8 (encoding a subunit of αvβ8), an integrin required for TGFβ activation. 131,221,222 However, oral tolerance is maintained in animals lacking IRF8-dependent cDC1, suggesting a level of redundancy in intestinal iTreg induction. 31,221,223 Experiments in which ovalbumin-specific CD4+ T cells were co-cultured with various mesenteric LN cDC subsets pulsed with ovalbumin peptide showed that CD103+ CD11b+ migDC2 and CD8α+ resDC were also capable of inducing an iTreg differentiation program, albeit to a lesser extent than CD103+ CD11b− migDC1. 221

Redundancy in DC subset instruction of iTreg differentiation is further exemplified in the skin where LC and cDC2 also have demonstrable roles in Treg induction. The proximity of epidermal LC to commensal microbes colonizing the surface of the skin has led to the proposal that the main function of LC is to induce tolerant responses. Indeed, in animals where MHCII expression was restricted to LC, epicutaneous immunization failed to induce effector or memory CD4+ T cell responses. 224 Further, other studies have shown that depletion of LC reduces Treg numbers and improves effector immune responses in a Leishmania major model. 225 LC were also found to mediate the induction of Treg following skin exposure to ionizing radiation. 226 In the skin, RALDH2 expression is greatest within the dermal cDC2 population, which were also found to promote iTreg induction ex vivo. 214

The signals involved in promoting tolerogenic functions of DC are currently unclear. NFκB signaling may be involved as DC-specific deletion of IKKβ impairs Treg induction, resulting in spontaneous autoimmunity. 227 The observation that IKKβ deficiency also reduces the accumulation of tissue-derived cDC in LNs suggests that NFκB signaling may regulate cDC migration rather than a tolerogenic program specifically. 227 Instead, adaptation to the tissue microenvironment may be important for initiating a tolerogenic cDC phenotype. TGFβR, retinoic acid, and MyD88 signaling are required for optimal Itgb8 expression by intestinal cDC1 and are sufficient to promote Itgb8 expression by splenic cDC1 ex vivo. 222 Further, Aldh1a2 expression is specifically enriched in cDC1 situated in the proximal intestine where iTreg induction is most prominent, indicating strong regionalization of tolerogenic programs within cDC1. 45 These data suggest that tolerogenic programming likely occurs in the tissue prior to migration, which may explain the largely concordant nature of transcriptional changes upon homeostatic or immunogenic maturation of cDC1 populations. 228

Instruction of Tfh differentiation

Tfh cells are a specialized Th cell subset that localize to B cell areas within secondary lymphoid organs where they support germinal center formation, affinity maturation, and antibody class switching (recently review in ref. 229 ). The differentiation pathway of Tfh cells is a multistep process that generally requires signals from both DC and B cells. 230 IL-6 and inducible co-stimulator (ICOS) signaling initiate the Tfh differentiation program by promoting the expression of Tfh-defining proteins, including BCL6, CXCR5, and IL-21. 231,232,233,234,235 An IL-21 autocrine signaling loop further supports their differentiation. 235 IFN-I, 236 IL-27, 237 IL-1β, 238 OX40, 239 and Notch signaling 240 can also support Tfh differentiation in vivo. In contrast, IL-2 is a potent inhibitor of Tfh differentiation 241,242 and Tfh-inducing cDC express the IL-2 receptor (CD25) in order to limit the availability of local IL-2. 243

DC are thought to play an important role in directing the initial phases of Tfh differentiation, with B cells providing subsequent signals to reinforce the Tfh program. However, a recent study has challenged this notion in the context of Plasmodium infection where cDC were reported to be dispensable and B cells necessary for the generation of antigen-specific Tfh responses. 244 Nevertheless, most cDC subsets have the capacity to induce Tfh differentiation in the appropriate conditions (recently reviewed in ref. 245 ) and cDC2 populations are necessary for regulating Tfh differentiation and humoral responses in a number of settings. 98,140,243,246,247,248,249 Several mouse models in which cDC2 were specifically depleted report a reduction in Tfh, germinal center B cells, and antibody titers following an immunization or infection protocol. 140,246,247,249 In humans, cDC2 isolated from tonsils were identified as the most effective DC subset at inducing Tfh polarization. 250 These data suggest that cDC2 support optimal Tfh differentiation in both mice and humans. Interestingly, cDC2 can also have a role in limiting Tfh and antibody responses in the absence of sufficient adjuvanticity. This function is performed by CD301b+ cDC2 and likely serves to prevent the generation of autoantibodies and restrict the generation of antibodies against allergens. 251

LC and cDC1 also have the capacity to induce Tfh differentiation, but this only appears to be efficient if antigen is directly targeted to these cell types with Clec9A or Langerin antibodies. 252,253,254,255 In experiments employing untargeted immunization protocols, LC only partially contributed to Tfh responses, 256 and there was no documented defect in Tfh differentiation or antibody responses in animals lacking cDC1. 140,246,247,249,256 The role of monocyte-derived cells, including moDC, in Tfh responses is less well defined, with examples of monocytes supporting, inhibiting or having no effect on Tfh numbers or antibody responses depending on the model being assessed. Depletion of monocyte-derived cells had no impact on antibody production in Salmonella infected mice 135 or the number of germinal center B cells in papain immunized mice, 251 suggesting that cells other than moDC are supporting Tfh responses in these animals. In other models, moDC are shown to negatively regulate Tfh differentiation. Monocyte depletion was associated with increased Tfh differentiation at the expense of Th1 differentiation following Plasmodium infection, 134 suggesting that monocyte-derived signals may regulate Th1/Tfh bifurcation. 134 There is also evidence that monocytes are required to provide critical Tfh-inducing factors in some settings. MoDC-derived IL-6 boosted Tfh responses in a CpG-B immunization model 257 and IL-1β derived from CX3CR1+ patrolling monocytes was required for Tfh differentiation following administration of heat-killed E. coli. 238 Together, these studies underscore the context-specific nature of the cell types involved in Tfh differentiation and the extent of cellular redundancy in this pathway.

As mentioned above, a number of redundant signals from cDC, monocytes, and B cells are involved in Tfh differentiation, which makes defining a “Tfh-inducing” profile difficult. One of the most critical factors for Tfh differentiation are early co-stimulatory interactions between DC and naive CD4+ T cells. DC-dependent ICOS signaling is required to induce BCL6 and CXCR5 in CD4+ T cells within the first few days of infection. 231 Similarly, cDC expression of CD40, 258 OX40L, 239,248,259 and Notch ligands 240 support Tfh differentiation to varying degrees. The non-canonical NFκB pathway is required for cDC2 expression of ICOSL and OX40L following polyIC stimulation, 248 and B-cell expression of ICOSL, 260 suggesting that this pathway may facilitate Tfh priming.

In addition to co-stimulation, DC promote Tfh responses through IL-6, with IL-6-KO DC inefficient at promoting IL-21+ Tfh cells. 261,262 Early IFN-I is an important inducer of DC-derived IL-6 263 and IFNAR deficiency in the DC compartment leads to blunted Tfh responses after VSV infection. 262 TRIF-dependent signaling in monocytes has been implicated in endowing these cells with the capacity to induce Tfh differentiation through production of IFN-I and inflammasome activation. 238 T cell intrinsic expression of IFNAR and IL-1Rβ was required for optimal Tfh differentiation in this model, 238 suggesting that IFN-I supports Tfh responses through actions on DC and T cells. This may explain the IFN-I-dependent enhancement of Tfh cell and germinal center responses in animals co-administered dsRNA with an influenza vaccine. 264

Finally, given that co-localization of pre-Tfh with B cells is a requirement for full Tfh differentiation, 265 chemokine signaling is an important factor in determining Tfh fate. CXCR5 expression mediated by ICOS signaling occurs within two cell divisions and is necessary for positioning pre-Tfh near B-cell areas. 231 In their study, Lonnberg et al. used pseudo-time modeling of scRNASeq data to show Plasmodium-specific Th cells co-express Cxcr3 and Cxcr5 prior to Th1/Tfh bifurcation. This observation coupled with their finding that depletion of monocyte-derived cells favors a Tfh fate over a Th1 fate led them to propose that IFN-dependent moDC production of CXCR3 ligands may act to limit Tfh differentiation by preferentially recruiting antigen-specific CXCR3+ CXCR5+ Th cells to a niche that supports Th1 differentiation. 134 This proposal is supported by data demonstrating a requirement for Th cells to locate to areas rich in CXCR3 ligands for optimal Th1 differentiation. 151,152 Therefore, chemokine gradients generated by DC and monocytes at the time of CD4+ T cell priming may play a key role in Tfh vs. Th differentiation.

The authors declare no competing financial interests.

This work was supported by The Belgian Program in Interuniversity Poles of Attraction Initiated by the Belgian State, Prime Minister’s office, Science Policy Programming by a Research Concerted Action of the Communauté Francaise de Belgique by a grant from the Fonds Jean Brachet and research credit from the National Fund for Scientific Research (FNRS), Belgium. F.A. is a Research Associate at the FNRS. D.D. was recipient of a research fellowship from the FNRS/Télévie and from the Fond David et Alice Van Buuren, Belgium. M.H. was supported by a Belgian FRIA fellowship. The authors thank Caroline Abdelaziz and Véronique Dissy for animal care and for technical support and Kris Thielemans (Vrije Universiteit Brussel) for generously providing the recombinant GM-CSF.

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Major Histocompatibility Complex Molecules

The major histocompatibility complex (MHC) is a collection of genes coding for MHC molecules found on the surface of all nucleated cells of the body. In humans, the MHC genes are also referred to as human leukocyte antigen (HLA) genes. Mature red blood cells, which lack a nucleus, are the only cells that do not express MHC molecules on their surface.

There are two classes of MHC molecules involved in adaptive immunity, MHC I and MHC II (Figure 1). MHC I molecules are found on all nucleated cells they present normal self-antigens as well as abnormal or nonself pathogens to the effector T cells involved in cellular immunity. In contrast, MHC II molecules are only found on macrophages, dendritic cells, and B cells they present abnormal or nonself pathogen antigens for the initial activation of T cells.

Both types of MHC molecules are transmembrane glycoproteins that assemble as dimers in the cytoplasmic membrane of cells, but their structures are quite different. MHC I molecules are composed of a longer α protein chain coupled with a smaller β2 microglobulin protein, and only the α chain spans the cytoplasmic membrane. The α chain of the MHC I molecule folds into three separate domains: α1, α2 and α3. MHC II molecules are composed of two protein chains (an α and a β chain) that are approximately similar in length. Both chains of the MHC II molecule possess portions that span the plasma membrane, and each chain folds into two separate domains: α1 and α2, and β1, and β2. In order to present abnormal or non-self-antigens to T cells, MHC molecules have a cleft that serves as the antigen-binding site near the “top” (or outermost) portion of the MHC-I or MHC-II dimer. For MHC I, the antigen-binding cleft is formed by the α1 and α2 domains, whereas for MHC II, the cleft is formed by the α1 and β1 domains (Figure 1).

Figure 1. MHC I are found on all nucleated body cells, and MHC II are found on macrophages, dendritic cells, and B cells (along with MHC I). The antigen-binding cleft of MHC I is formed by domains α1 and α2. The antigen-binding cleft of MHC II is formed by domains α1 and β1.

Think about It


T follicular helper (Tfh) cells play an essential role in regulating the GC reaction and, consequently, the generation of high-affinity antibodies and memory B cells. Therefore, Tfh cells are critical for potent humoral immune responses against various pathogens and their dysregulation has been linked to autoimmunity and cancer. Tfh cell differentiation is a multistep process, in which cognate interactions with different APC types, costimulatory and coinhibitory pathways, as well as cytokines are involved. However, it is still not fully understood how a subset of activated CD4 + T cells begins to express the Tfh cell-defining chemokine receptor CXCR5 during the early stage of the immune response, how some CXCR5 + pre-Tfh cells enter the B-cell follicles and mature further into GC Tfh cells, and how Tfh cells are maintained in the memory compartment. In this review, we discuss recent advances on how antigen and cognate interactions are important for Tfh cell differentiation and long-term persistence of Tfh cell memory, and how this is relevant to the current understanding of COVID-19 pathogenesis and the development of potent SARS-CoV-2 vaccines.


Our observations provide mechanisms underlying two recent observations. Ulmer et al. (18) showed that F1(H-2 d × H-2 k ) mice injected with a myoblast cell line (H-2 k ) transfected with a foreign gene developed H-2 d – and H-2 k – restricted immunity. Corr et al. (19) used chimeric mice, in which the haplotype of bone marrow was mismatched with the haplotype of somatic cells at the site of injection, to demonstrate that the priming of specific CTLs was driven by the MHC from the bone marrow–derived APCs.

First, we demonstrated that a VH–TB polypeptide, encoded by a DNA vaccine, is secreted by G7/ p VH–TB myoblasts and can be processed and presented by other APCs to the HA110-120–specific T cells. Second, our in vivo results showed that the dendritic cells from mice immunized with p VH–TB were able to activate T cells, whereas B cells were not. These data indicate that dendritic cells can play a crucial role in triggering immune responses subsequent to DNA immunization. Third, we found that, in spite of the paucity of APCs in muscles, dendritic but not B cells were transfected in vivo with p VH–TB plasmid. Condon et al. (20) have obtained cytological evidence for the in vivo expression of a protein encoded by a foreign gene in dendritic cells. Our data demonstrate for the first time that purified dendritic cells carry plasmid DNA and present the corresponding CD4 T helper epitope to antigen-specific T cells.

Likewise, after intradermal injection of DNA, the p VH– TB plasmid was detected in both MHC class II–positive and MHC class II–negative skin cells. In vivo transfection of skin cells has been reported (21), but the ability of these cells to activate specific T cells has not been investigated. Our results demonstrated that only MHC class II–positive dendritic cells were able to activate the specific CD4 T cells.

We attempted to estimate the frequency of dendritic cells that could express genes encoded by the DNA vaccine. We injected mice with DNA for a green fluorescence protein that produced bright fluorescence upon transfection of cultured cell lines, using either a CMV or HIV-1 promoter. 0–5 h after injection, the skin was removed and the emigrated dendritic cells were collected over a 5-d culture period. However, at no time could we detect fluorescent dendritic cells by FACS ® or by fluorescence microscopy, probably because the frequency of DNA-bearing dendritic cells was very low (<1/200 cells).

In conclusion, we have found that dendritic cells can play a crucial role in the initiation of T helper immune responses by DNA immunization. Subsequent to intramuscular or subcutaneous immunization with DNA, myocytes or MHC class II–negative dermal cells can be transfected and can secrete the protein encoded by the foreign gene, which is then presented by dendritic but not by most B cells. In addition, the dendritic cells carry plasmid DNA and thereby may be able to express vaccine epitopes directly.

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