Background TH 2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine–mediated inflammation and pathology. A new ...T-cell subset, follicular helper T (TFH ) cells, is specialized in supporting B-cell maturation and antibody production. Objective We sought to investigate the roles of TFH cells in allergic immune responses. Methods Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. Results We observed the development of IL-4–producing TFH cells and TH 2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. TFH and TH 2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. TFH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when TH 2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4+ T cells resulted in a marked reduction in TFH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. Conclusion TFH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4–producing CD4+ T cells, namely TFH and Th2 cells.
Abstract
This Pillars of Immunology article is a commentary on “A new T-cell receptor gene located within the alpha locus and expressed early in T-cell differentiation,” a pivotal article written by ...Y.-H. Chien, M. Iwashima, K. B. Kaplan, J. F. Elliott, and M. M. Davis, and published in Nature, in 1987. https://www.nature.com/articles/327677a0.
Development of high-affinity Abs in the germinal center (GC) is dependent on a specialized subset of T cells called "T follicular helper" (TFH) cells that help select Ag-specific B cells. A second T ...cell subset, T follicular regulatory (TFR) cells, can act as repressors of the GC and Ab response but can also provide a helper function for GC B cells in some contexts. Recent studies showed that, apart from their traditional helper role, TFH cells can also act as repressors of the Ab response, particularly for IgE responses. We review how both TFH and TFR cells express helper and repressor factors that coordinately regulate the Ab response and how the line between these two subsets is less clear than initially thought. Thus, TFH and TFR cells are interconnected and have "nonbinary" functions. However, many questions remain about how these critical cells control the Ab response.
Follicular helper T (Tfh) cells are necessary for germinal center (GC) formation and within the GC, provide key signals to B cells for their differentiation into plasmablasts and plasma cells that ...secrete high-affinity and isotype-switched antibody (Ab). A specialized subset of Foxp3
T cells termed T follicular regulatory (Tfr) cells, also regulate the differentiation of Ab-secreting cells from the GC. Tfr-cell function in the GC is not well understood, however, the dominant paradigm currently is that Tfr cells repress excessive Tfh and GC B cell proliferation and help promote stringent selection of high-affinity B cells. A mouse model where the Bcl6 gene is specifically deleted in Foxp3
T cells (Bcl6FC mice) allows the study of Tfr cell function with more precision than other approaches. Studies with this model have shown that Tfr cells play a key role in maintaining GC B cell proliferation and Ab levels. Part of the mechanism for this positive "helper" effect of Tfr cells on the GC is Tfr cell-derived IL-10, which can promote B cell growth and entry into the dark zone of the GC. Recent studies on Tfr cells support a new paradigm for Tfr cell function in the GC reaction. Here, we review studies on Tfr cell functions and discuss the evidence that Tfr cells can have a major helper role in the GC-dependent Ab response.
Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the ...type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and elucidate mechanisms of commensal IgA targeting. We found that residence in the small intestine, rather than bacterial identity, dictated induction of specific IgA. Most commensals elicited strong T-independent (TI) responses that originated from the orphan B1b lineage and from B2 cells, but excluded natural antibacterial B1a specificities. Atypical commensals including segmented filamentous bacteria and Mucispirillum evaded TI responses but elicited T-dependent IgA. These data demonstrate exquisite targeting of distinct commensal bacteria by multiple layers of humoral immunity and reveal a specialized function of the B1b lineage in TI mucosal IgA responses.
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•IgA predominantly targets commensal bacteria that reside in the small intestine•Most commensal bacteria elicit strong T-independent IgA responses•A minor subset of bacteria evade T-independent IgA and elicit T-dependent responses•The orphan B1b lineage is a prominent source of commensal-specific IgA
Bendelac and colleagues find that homeostatic IgA responses target commensal bacteria that reside in the small intestine but exclude bacteria indigenous to the colon. Most commensals are targeted by T-independent IgA derived predominantly from the orphan B1b lineage, but atypical subsets evade T-independent responses and elicit T-dependent IgA.
Little is currently known regarding the immunologic mechanism(s) that initiate peanut allergy. Notably, peanut proteins have been detected in house dust, and their levels correlate with peanut ...allergy prevalence.
This study aimed to develop a new mouse model for peanut allergy and to investigate the immunologic mechanisms involved in peanut allergen sensitization.
To mimic environmental exposure, naive mice were exposed to peanut flour by inhalation for up to 4 weeks. We then analyzed serum levels of IgE antibody and challenged mice with peanut proteins. Immunological mechanisms involved in sensitization were analyzed using cytokine reporter mice, an adoptive cell transfer model, and gene knockout mice.
When exposed to peanut flour by inhalation, both BALB/c and C57BL/6 mice developed peanut allergy, as demonstrated by the presence of peanut-specific IgE antibodies and manifestation of acute anaphylaxis on challenge. A large number of follicular helper T (Tfh) cells were also detected in draining lymph nodes of allergic mice. These cells produced IL-4 and IL-21, and they more robustly promoted peanut-specific IgE production than Th2 cells did. Genetic depletion of Tfh cells decreased IgE antibody levels and protected mice from anaphylaxis, without affecting Th2 cells. Furthermore, peanut flour exposure increased lung levels of IL-1α and IL-1β, and mice deficient in the receptor for these cytokines showed a significant decrease in Tfh cells compared with in wild-type mice.
Tfh cells play a key role in peanut allergy, and the IL-1 pathway is involved in the Tfh response to peanut allergen exposure.
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High-affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High-affinity Abs are formed by successive rounds of selection of Ag-specific B cells in the germinal ...center (GC); however, several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the "indirect switching pathway" for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high-affinity IgE develops in the GC, but we did not test the indirect switching model. In this study, we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that, as expected, IgG1 Abs had decreased affinity, but unexpectedly, the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high-affinity IgE. Thus, in a food allergy response, high-affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.
The production of antibody is precisely controlled during the germinal center (GC) reaction. This process is dependent on the help from follicular T helper (Tfh) cells to germinal center (GC) B cells ...and is regulated by regulatory follicular T helper (Tfr) cells. How Tfr cells develop and how their suppressive activity functions are not well understood. Here, we found that Stat3 is indispensible for Tfr cell differentiation. After immunization with Sheep Red Blood Cells (SRBC), the loss of Tfr cells caused by deletion of Stat3 in Treg cells does not affect the size of Tfh or GC B cell population, but rather leads to strongly enhanced production of antigen-specific IgG1 and IgG2b. In Peyer's patches (PPs) in the gut, we found that Stat3 expression in Treg cells is also required for Tfr cell formation to commensal organisms. However, loss of Tfr cells in the gut did not affect the numbers of Tfh cells and GC B cells, nor affect IgG1 or IgA switching by GC B cells. Overall, our study has uncovered unique roles of Stat3 in Tfr cell differentiation and the regulation of the antibody response.
Follicular helper T (Tfh) cells provide crucial help to germinal center B (GCB) cells for proper antibody production, and a specialized subset of regulatory T cells, follicular regulatory T (Tfr) ...cells, modulate this process. However, Tfr‐cell function in the GC is not well understood. Here, we define Tfr cells as a CD4+ Foxp3+ CXCR5hi PD‐1hi CD25low TIGIThigh T‐cell population. Furthermore, we have used a novel mouse model (“Bcl6FC”) to delete the Bcl6 gene in Foxp3+ T cells and thus specifically deplete Tfr cells. Following immunization, Bcl6FC mice develop normal Tfh‐ and GCB‐cell populations. However, Bcl6FC mice produce altered antigen‐specific antibody responses, with reduced titers of IgG and significantly increased IgA. Bcl6FC mice also developed IgG antibodies with significantly decreased avidity to antigen in an HIV‐1 gp120 “prime‐boost” vaccine model. In an autoimmune lupus model, we observed strongly elevated anti‐DNA IgA titers in Bcl6FC mice. Additionally, Tfh cells from Bcl6FC mice consistently produce higher levels of Interferon‐γ, IL‐10 and IL‐21. Loss of Tfr cells therefore leads to highly abnormal Tfh‐cell and GCB‐cell responses. Overall, our study has uncovered unique regulatory roles for Tfr cells in the GC response.
T‐follicular regulatory (TFR) cells express high levels of the inhibitory receptor TIGIT. TFR cells decrease production of helper cytokines by T‐follicular helper (TFH) cells. TFR cells help shape the antibody response in the germinal center by promoting high affinity IgG and decreasing IgA production.
Neutrophils are vital for antimicrobial defense; however, their role during viral infection is less clear. Furthermore, the molecular regulation of neutrophil fate and function at the viral infected ...sites is largely elusive. Here we report that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza A virus (IAV) infection. In contrast to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cretransgenic, reporter, and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or lung macrophages, attenuated host inflammation and morbidity following IAV infection. Mechanistically, BCL6 bound to the neutrophil gene loci involved in cellular apoptosis in cells specifically at the site of infection. As such, BCL6 disruption resulted in increased expression of apoptotic genes in neutrophils in the respiratory tract, but not in the circulation or bone marrow. Consequently, BCL6 deficiency promoted tissue neutrophil apoptosis. Partial neutrophil depletion led to diminished pulmonary inflammation and decreased host morbidity. Our results reveal a previously unappreciated role of BCL6 in modulating neutrophil apoptosis at the site of infection for the regulation of host disease development following viral infection. Furthermore, our studies indicate that tissue-specific regulation of neutrophil survival modulates host inflammation and tissue immunopathology during acute respiratory viral infection.
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