Differentiation Of Follicular Helper Research Articles

IL-15 Complex-Induced IL-10 Enhances Plasmodium-specific CD4+ T Follicular Helper Differentiation and Antibody Production.

Malaria, which results from infection with Plasmodium parasites, remains a major public health problem. Although humans do not develop long-lived, sterilizing immunity, protection against symptomatic disease develops after repeated exposure to Plasmodium parasites and correlates with the acquisition of humoral immunity. Despite the established role Abs play in protection from malaria disease, dysregulated inflammation is thought to contribute to the suboptimal immune response to Plasmodium infection. Plasmodium berghei ANKA (PbA) infection results in a fatal severe malaria disease in mice. We previously demonstrated that treatment of mice with IL-15 complex (IL-15C; IL-15 bound to an IL-15Rα-Fc fusion protein) induces IL-10 expression in NK cells, which protects mice from PbA-induced death. Using a novel MHC class II tetramer to identify PbA-specific CD4+ T cells, in this study we demonstrate that IL-15C treatment enhances T follicular helper (Tfh) differentiation and modulates cytokine production by CD4+ T cells. Moreover, genetic deletion of NK cell-derived IL-10 or IL-10R expression on T cells prevents IL-15C-induced Tfh differentiation. Additionally, IL-15C treatment results in increased anti-PbA IgG Ab levels and improves survival following reinfection. Overall, these data demonstrate that IL-15C treatment, via its induction of IL-10 from NK cells, modulates the dysregulated inflammation during Plasmodium infection to promote Tfh differentiation and Ab generation, correlating with improved survival from reinfection. These findings will facilitate improved control of malaria infection and protection from disease by informing therapeutic strategies and vaccine design.

Stepwise differentiation of follicular helper T cells reveals distinct developmental and functional states

Follicular helper T (Tfh) cells are essential for the formation of high affinity antibodies after vaccination or infection. Although the signals responsible for initiating Tfh differentiation from naïve T cells have been studied, the signals controlling sequential developmental stages culminating in optimal effector function are not well understood. Here we use fate mapping strategies for the cytokine IL-21 to uncover sequential developmental stages of Tfh differentiation including a progenitor-like stage, a fully developed effector stage and a post-effector Tfh stage that maintains transcriptional and epigenetic features without IL-21 production. We find that progression through these stages are controlled intrinsically by the transcription factor FoxP1 and extrinsically by follicular regulatory T cells. Through selective deletion of Tfh stages, we show that these cells control antibody dynamics during distinct stages of the germinal center reaction in response to a SARS-CoV-2 vaccine. Together, these studies demonstrate the sequential phases of Tfh development and how they promote humoral immunity.

E3 ubiquitin ligase STUB1 affects the mTORC1 pathway through p62 and participates in regulating the differentiation of follicular helper T cells in rheumatoid arthritis

ObjectiveThe abnormal expansion of Tfh cells plays a key role in chronic inflammation of RA joint. We speculated that STUB1 is an important regulatory factor in promoting the differentiation of Tfh cells in RA. Content and methodsThe proportion of Tfh cells and the level of STUB1 in Tfh cells was measured. CD4+T cells were isolated from PBMCs of RA patients, and the percentage of Tfh cells was detected after up- or down-regulating the expression of STUB1. The levels of mTORC1 pathway activator p-mTOR and p-S6K were measured by Western blot. The ubiquitination of p62 by STUB1 and its ubiquitination type as well as the activation of mTORC1 was detected in vitro, and the activation of the mTORC1 and the differentiation of Tfh cells was detected in STUB1-upregulated CD4+ T cells with overexpressed p62. ResultsThe level of STUB1 is elevated in Tfh cells of patients. Up-regulation of STUB1 can promote the differentiation of Tfh cells. STUB1 promotes the degradation of p62 via K48-linked ubiquitination and promotes the activation of mTORC1. Overexpression of p62 can reverse the promoting effect of STUB1 on the differentiation of Tfh cells and the activation of mTORC1. ConclusionSTUB1 can promote the differentiation of Tfh cells in RA by mediating the activation of mTORC1 pathway through ubiquitination of p62.

Targeting Bcl-6 prevents sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation in mice.

Chronic graft-versus-host disease (cGVHD) is the most common cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). CD4+ follicular helper T (Tfh) cells, specialized providers of T cell help to B cells, play a vital role in GVHD pathogenesis. B-cell lymphoma-6 (Bcl-6) transcription factor has been shown to be required for Tfh-mediated germinal center reactions. In this study, we would like to evaluate the effect of Bcl-6 on Tfh function in sclerodermatous cGVHD and the efficacy of Bcl-6 inhibitors (Bcl-6i) for treating a minor histocompatibility complex (miHC) mismatch model of sclerodermatous cGVHD (scl-cGVHD). A minor histocompatibility haploidentical model of scl-cGVHD was established and received intraperitoneal injection of 79-6, a small-molecule inhibitor of Bcl-6. The clinical manifestations and survival times of cGVHD mice were recorded. The histological assessment was performed by hematoxylin-eosin (HE) and Masson's trichrome staining on the skin and lung tissues. Tfh cells and germinal center B cells in the spleen and peripheral blood were detected by flow cytometry. The cellular markers were immunostained in different organs. ELISA was performed to detect cytokine secretion. Bcl-6 inhibition by 79-6 improved the clinical manifestation of scl-cGVHD mice and prolonged their survival. The histopathologic damage, particular the fibrotic changes of scl-cGVHD mice was significantly relieved after 79-6 treatment. Furthermore, 79-6 treatment not only suppressed the development and function of Tfh and Tph cells in the peripheral blood, but also reduced the survival of Tfh cells in the spleen. Moreover, 79-6 decreased the frequency of GC plasmocytes accompanied by a reduction in IL-21. Our study demonstrates that Bcl-6 inhibitor could prevent murine sclerodermatous chronic graft-versus-host disease by abrogating T follicular helper differentiation and suppressing the function of GC B cells, indicating that Bcl-6 inhibition may be a potential treatment for patients with cGVHD.

The hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells.

Follicular helper T (TFH ) cells are essential for inducing germinal centre (GC) reactions to mediate humoral adaptive immunity and antiviral effects, but the mechanisms of TFH cell differentiation remain unclear. Here, we found that the hippo kinase MST1 is critical for TFH cell differentiation, GC formation, and antibody production under steady-state conditions and viral infection. MST1 deficiency intrinsically enhanced TFH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signalling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed TFH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for TFH cell differentiation induced by Mst1-/- . Thus, our findings identify a previously unrecognized relationship between hippo kinase MST1 signalling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signalling in reprogramming TFH cell differentiation.

Toll-Like Receptor 4 Regulates Rabies Virus-Induced Humoral Immunity through Recruitment of Conventional Type 2 Dendritic Cells to Lymph Organs.

Rabies, caused by rabies virus (RABV), is fatal to both humans and animals around the world. Effective clinical therapy for rabies has not been achieved, and vaccination is the most effective means of preventing and controlling rabies. Although different vaccines, such as live attenuated and inactivated vaccines, can induce different immune responses, different expressions of pattern recognition receptors (PRRs) also cause diverse immune responses. Toll-like receptor 4 (TLR4) is a pivotal PRR that induces cytokine production and bridges innate and adaptive immunity. Importantly, TLR4 recognizes various virus-derived pathogen-associated molecular patterns (PAMPs) and virus-induced damage-associated molecular patterns (DAMPs), usually leading to the activation of immune cells. However, the role of TLR4 in the humoral immune response induced by RABV has not yet been revealed. Based on TLR4-deficient (TLR4-/-) and wild-type (WT) mouse models, we report that TLR4-dependent recruitment of the conventional type 2 dendritic cells (CD8α- CD11b+ cDC2) into secondary lymph organs (SLOs) is critical for antigen presentation. cDC2-initiated differentiation of follicular helper T (Tfh) cells promotes the proliferation of germinal center (GC) B cells, the formation of GCs, and the production of plasma cells (PCs), all of which contribute to the production of RABV-specific IgG and virus-neutralizing antibodies (VNAs). Collectively, our work demonstrates that TLR4 is necessary for the recruitment of cDC2 and for the induction of RABV-induced humoral immunity, which is regulated by the cDC2-Tfh-GC B axis. IMPORTANCE Vaccination is the most efficient method to prevent rabies. TLR4, a well-known immune sensor, plays a critical role in initiating innate immune response. Here, we found that TLR4-deficient (TLR4-/-) mice suppressed the induction of humoral immune response after immunization with rabies virus (RABV), including reduced production of VNAs and RABV-specific IgG compared to that occurred in wild-type (WT) mice. As a consequence, TLR4-/- mice exhibited higher mortality than that of WT mice after challenge with virulent RABV. Importantly, further investigation found that TLR4 signaling promoted the recruitment of cDC2 (CD8α+ CD11b-), a subset of cDCs known to induce CD4+ T-cell immunity through their MHC-II presentation machinery. Our results imply that TLR4 is indispensable for an efficient humoral response to rabies vaccine, which provides new insight into the development of novel rabies vaccines.

TET2 Regulates CD4+ T Follicular Helper Differentiation

DNA methylation is a key epigenetic mechanism that controls T cell differentiation. The ten-eleven translocation (TET) family of methylcytosine dioxygenases converts 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and other oxidized methylcytosines. TET2 mutations have been identified in angioimmunoblastic T cell lymphomas (AITL), which are derived from CD4+ T follicular helper (TFH) cells. CD4+ TFH cells are a T cell subset that provides essential help for the germinal center reaction and class switching. Here we demonstrate that TET2 regulates murine CD4+ TFH differentiation in vivo . At steady-state, mice with a T cell specific deletion of TET2 (TET2cKO) have intact thymic and peripheral T cell populations. Following acute viral infection with LCMV-Armstrong, TET2 loss promotes CD4+ TFH cell expansion. Examination of the Peyer's patches (a site of TFH differentiation in response to gut microbes) of wild-type and TET2cKO mice demonstrate an increase in the absolute number of the CD4+ TFH (CXCR5+PD1+) population in TET2cKO mice. Furthermore, there is an increase in the frequency and absolute number of germinal center B cells (characterized by PNA+GL7+ B cells) and an increase in IgA+ B cells in the Peyer's patches of TET2cKO mice compared to wild-type mice. Ongoing studies are examining the mechanism by which TET2 controls CD4+ TFH expansion. Our data indicate that TET2 is an important regulator of CD4+ TFH cells. Understanding the role of TET2 in normal CD4+ TFH differentiation and its contribution to T cell lymphomagenesis will lead to important insights into the epigenetic and molecular mechanisms underlying AITL pathogenesis DisclosuresNo relevant conflicts of interest to declare.

Natural killer cells promote the differentiation of follicular helper T cells instead of inducing apoptosis in myasthenia gravis

Recent evidence has shown that natural killer (NK) cells have an immunoregulatory function in the pathogenesis of myasthenia gravis (MG). In this study, the phenotype and function of NK cell subsets in peripheral blood of new-onset MG (N-MG) and stable MG (S-MG) patients were explored. Circulating CD56dim and CD56bright NK cells were increased and decreased, respectively, in patients with N-MG and S-MG compared with healthy control (HC). Moreover, all circulating NK cell subsets from N-MG patients showed significantly lower expression of activating receptor NKG2D and production of Interferon (IFN) -γ than that from HC. The killing effects of NK cells on CD4+ T cells and Tfh cells were impaired in MG patients, whereas, they promoted the differentiation and activation of Tfh cells. These data indicated that the immune-regulation of NK cells on CD4+ T cells and Tfh cells in MG patients was abnormal, which may contribute to the immune-pathological mechanism of MG.

ICOS signaling promotes a secondary humoral response after re-challenge with Plasmodiumchabaudi chabaudi AS.

The co-stimulatory molecule ICOS is associated with the induction and regulation of T helper cell responses, including the differentiation of follicular helper T (Tfh) cells and the formation and maintenance of memory T cells. However, the role of ICOS signaling in secondary immune responses is largely unexplored. Here we show that memory T cell formation and maintenance are influenced by persistent infection with P. chabaudi chabaudi AS infection, as memory T cell numbers decline in wild-type and Icos-/- mice after drug-clearance. Following drug-clearance Icos-/- mice display a relapsing parasitemia that occurs more frequently and with higher peaks compared to wild-type mice after re-challenge. The secondary immune response in Icos-/- mice is characterized by significant impairment in the expansion of effector cells with a Tfh-like phenotype, which is associated with a diminished and delayed parasite-specific Ab response and the absence of germinal centers. Similarly, the administration of an anti-ICOSL antagonizing antibody to wild-type mice before and after reinfection with P. c. chabaudi AS leads to an early defect in Tfh cell expansion and parasite-specific antibody production, confirming a need for ICOS-ICOSL interactions to promote memory B cell responses. Furthermore, adoptive transfer of central memory T (TCM) cells from wild-type and Icos-/- mice into tcrb-/- mice to directly evaluate the ability of TCM cells to give rise to Tfh cells revealed that TCM cells from wild-type mice acquire a mixed Th1- and Tfh-like phenotype after P. c. chabaudi AS infection. While TCM cells from Icos-/- mice expand and display markers of activation to a similar degree as their WT counterparts, they displayed a reduced capacity to upregulate markers indicative of a Tfh cell phenotype, resulting in a diminished humoral response. Together these findings verify that ICOS signaling in memory T cells plays an integral role in promoting T cell effector responses during secondary infection with P. c. chabaudi AS.

A Thpok-Directed Transcriptional Circuitry Promotes Bcl6 and Maf Expression to Orchestrate T Follicular Helper Differentiation

The generation of high-affinity neutralizing antibodies, the objective of most vaccine strategies, occurs in B cells within germinal centers (GCs) and requires rate-limiting "help" from follicular helper CD4+ T (Tfh) cells. Although Tfh differentiation is an attribute of MHC II-restricted CD4+ Tcells, the transcription factors driving Tfh differentiation, notably Bcl6, are not restricted to CD4+ Tcells. Here, we identified a requirement for the CD4+-specific transcription factor Thpok during Tfh cell differentiation, GC formation, and antibody maturation. Thpok promoted Bcl6 expression and bound to a Thpok-responsive region in the first intron of Bcl6. Thpok also promoted the expression of Bcl6-independent genes, including the transcription factor Maf, which cooperated with Bcl6 to mediate the effect of Thpok on Tfh cell differentiation. Our findings identify a transcriptional program that links the CD4+ lineage with Tfh differentiation, a limiting factor for efficient B cell responses, and suggest avenues to optimize vaccine generation.

Context-Dependent Role for T-bet in T Follicular Helper Differentiation and Germinal Center Function following Viral Infection

SUMMARYFollowing infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination.

The E3 ligase VHL promotes the differentiation of follicular helper T cells through glycolytic-epigenetic pathways

Abstract Follicular helper T (Tfh) cells are essential for germinal center formation and effective humoral immunity, which undergo different stages of development to become fully polarized. However, the detailed mechanisms of their regulation remain unsolved. Here we found that the E3 ubiquitin ligase VHL was required for Tfh cell development and function upon acute virus infection or antigen immunization. VHL acted through hypoxia-inducible factor (HIF)-1α-dependent glycolysis pathway to positively regulate early Tfh cell initiation. The enhanced glycolytic activity due to VHL deficiency was involved in the epigenetic regulation of ICOS expression, a critical molecule for Tfh cell development. By using the RNAi-based screen, we identified the glycolytic enzyme GAPDH as the key target for the reduced ICOS expression via m6A modification during Tfh cell initiation. Our results thus demonstrated that VHL-HIF-1α axis played an important role during the initiation of Tfh cell development through glycolytic-epigenetic reprogramming. Here we will discuss how immune signals and cell metabolic programs are linked to instruct Tfh cell initiation and function, which can provide some insight into rational vaccine design against human infectious diseases and therapeutic intervention of autoimmune diseases.

Therapeutic effects of baicalin on lupus nephritis in a lupus-prone mouse model and its regulatory role in follicular helper T cell differentiation

Objective To evaluate the therapeutic effect of baicalin on lupus nephritis in a lupus-prone mouse model, and to investigate its regulatory role in the differentiation of follicular helper T (Tfh) cells. Methods Eight 12-week-old female MRL/lpr lupus-prone mice were randomly and equally divided into two groups by a random number table i.e., baicalin group and control group intraperitoneally injected with 200 mg/kg baicalin sodium and chloride physiological solution, respectively, once every day for 4 weeks. After the end of treatment, Coomassie brilliant blue staining was performed to detect the level of 24-hour urine protein. Then, the mice were sacrificed, and the spleens were resected and weighed. Mononuclear cells were isolated from these spleens, and flow cytometry was conducted to determine the proportion of Tfh cells. Additionally, the kidneys were resected and subjected to hematoxylin and eosin (HE) staining for the evaluation of kidney impairment. Moreover, some other mononuclear cells were isolated from the spleens of the lupus-prone mice in the control group, and magnetic activated cell sorting (MACS) was performed to isolate naive CD4+ T cells, which were divided into 3 groups: blank control group receiving no treatment, induction group treated with 10 μg/L anti-interleukin (IL) -21 and anti-IL-6 antibodies and 3 μg/L anti-CD3 and anti-CD28 antibodies for 5 days, and intervention group additionally treated with 40 μmol/L baicalin for 5 days besides the above treatment. Then, 50 μg/L phorbol ester, 750 μg/L ionomycin and 20 mg/L brefeldin A were used to stimulate some cultured naive CD4+ T cells in the above groups. Flow cytometry was conducted to determine the proportion of CD4+CXCR5+PD-1+ cells and CD4+IL-21+ cells. Statistical analysis was carried out with SPSS20.0 software by using one-way analysis of variance (ANOVA) and student t test for the comparison of quantitative data between groups. Results The baicalin treatment could effectively improve the kidney impairment in the lupus-prone mice. Compared with the control group, the baicalin group showed significantly decreased 24-hour urine protein level ([1 416 ± 171] vs. [2 623 ± 278] μg/24 h, P = 0.022) , and significantly decreased proportion of Tfh cells in the spleen (12.6% ± 2.3% vs. 40.2% ± 1.1%, P = 0.005) . In vitro baicalin could further inhibit the differentiation of Tfh cells. Compared with the induction group, the intervention group showed significantly decreased proportion of CD4+CXCR5+PD-1+ Tfh cells (13.3% ± 0.8% vs. 17.6% ± 0.9%, P = 0.04) and CD4+IL-21+ cells (1.0% ± 0.4% vs. 2.7% ± 0.2%, P < 0.01) . Conclusion Baicalin can effectively ameliorate lupus nephritis, which may be associated with the inhibition of Tfh cell differentiation. Key words: Lupus erythematosus, systemic; Lupus nephritis; Baicalin; Disease models, animal; Follicular helper T cells; Interleukin-21

The histone methyltransferase EZH2 primes the early differentiation of follicular helper T cells during acute viral infection

Epigenetic modifications to histones dictate the differentiation of naïve CD4+ T cells into different subsets of effector T helper (TH) cells. The histone methyltransferase enhancer of zeste homolog 2 (EZH2) has been implicated in the mechanism regulating the differentiation of TH1, TH2 and regulatory T (Treg) cells. However, whether and how EZH2 regulates follicular helper T (TFH) cell differentiation remain unknown. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we observed abundant EZH2 expression and associated H3K27me3 modifications preferentially in the early committed virus-specific TFH cells compared to those in TH1 cells. Ablation of EZH2 in LCMV-specific CD4+ T cells leads to a selective impairment of early TFH cell fate commitment, but not late TFH differentiation or memory TFH maintenance. Mechanistically, EZH2 specifically stabilizes the chromatin accessibility of a cluster of genes that are important for TFH fate commitment, particularly B cell lymphoma 6 (Bcl6), and thus directs TFH cell commitment. Therefore, we identified the chromatin-modifying enzyme EZH2 as a novel regulator of early TFH differentiation during acute viral infection.

C5aR1 regulates T follicular helper differentiation and chronic graft-versus-host disease bronchiolitis obliterans.

CD4+ follicular helper T (Tfh) cells are specialized providers of T cell help to B cells and can function as pathogenic mediators of murine antibody-dependent chronic graft-versus-host disease (GvHD). Using a parent→F1 model of lupus-like chronic GvHD, in which Tfh cell and germinal center (GC) B cell differentiation occurs over 14 days, we demonstrate that absence of CD4+ T cell-expressed C5a receptor 1 (C5ar1) or pharmacological C5aR1 blockade abrogated generation/expansion of Tfh cells, GC B cells, and autoantibodies. In a Tfh cell-dependent model of chronic GvHD manifested by bronchiolitis obliterans syndrome (BOS), C5aR1 antagonism initiated in mice with established disease ameliorated BOS and abolished the associated differentiation of Tfh and GC B cells. Guided by RNA-sequencing data, mechanistic studies performed using murine and human T cells showed that C5aR1 signaling amplifies IL-6-dependent expression of the transcription factor c-MAF and the cytokine IL-21 via phosphorylating phosphokinase B (AKT) and activating the mammalian target of rapamycin (mTOR). In addition to linking C5aR1-initiated signaling to Tfh cell differentiation, our findings suggest that C5aR1 may be a useful therapeutic target for prevention and/or treatment of individuals with Tfh cell-dependent diseases, including those chronic GvHD patients who have anti-host reactive antibodies.

T6: ECM1 controls Th2 migration and promotes differentiation of follicular helper T cells by antagonizing IL‐2‐STAT5 pathway

American Journal of Reproductive ImmunologyVolume 80, Issue S1 p. 24-24 ABSTRACTS T6: ECM1 controls Th2 migration and promotes differentiation of follicular helper T cells by antagonizing IL-2-STAT5 pathway First published: 26 June 2018 https://doi.org/10.1111/aji.05_12981Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume80, IssueS1Special Issue: American-Sino Joint Meeting of Reproductive Immunology (ASRI-CSI 2018), June 28-1 July, 2018 Shanghai, ChinaJune 2018Pages 24-24 RelatedInformation

The adaptor molecule CD2AP in CD4 T cells modulates differentiation of follicular helper T cells during chronic LCMV infection.

CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogen infection. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that modulate CD4 T cell functions in response to viral infection or vaccine are incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2-associated protein (CD2AP) promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic lymphocytic choriomeningitis virus (LCMV) infection. The enhanced follicular helper differentiation is associated with extended duration of TCR signaling and enhanced cytokine production of CD2AP-deficient CD4 T cells specifically under TH1 conditions, while neither prolonged TCR signaling nor enhanced follicular helper differentiation was observed under conditions that induce other helper effector subsets. Despite the structural similarity between CD2AP and the closely related adaptor protein CIN85, we observed defective antibody-mediated control of chronic LCMV infection in mice lacking CIN85 in T cells, suggesting non-overlapping and potentially antagonistic roles for CD2AP and CIN85. These results suggest that tuning of TCR signaling by targeting CD2AP improves protective antibody responses in viral infection.

Regulation of TCR signaling by CD2AP in CD4 T cells modulates antibody responses to chronic LCMV infection

Abstract CD4 T cell-mediated help to CD8 T cells and B cells is a critical arm of the adaptive immune system required for control of pathogens. CD4 T cells express cytokines and co-stimulatory molecules that support a sustained CD8 T cell response and also enhance generation of protective antibody by germinal center B cells. However, the molecular components that regulate CD4 T cell functions in response to viral infection or vaccine is incompletely understood. Here we demonstrate that inactivation of the signaling adaptor CD2AP promotes CD4 T cell differentiation towards the follicular helper lineage, leading to enhanced control of viral infection by augmented germinal center response in chronic LCMV infection. The enhanced follicular helper differentiation is associated with extended duration of TCR signaling and enhanced cytokine production of CD2AP-deficient CD4 T cells specifically under TH1 conditions, while neither prolonged TCR signaling nor enhanced follicular helper differentiation was observed under conditions that induce other helper effector subsets. These results suggest that tuning of TCR signaling by targeting CD2AP improved protective antibody responses in viral infection.

The Transcription Factor c-Maf Promotes the Differentiation of Follicular Helper T Cells.

Follicular helper T cells (Tfh) have been identified as the primary cell subpopulation regulating B cell responses in germinal centers, thus supporting high-affinity antibody production. Among the transcription factors orchestrating Tfh cell differentiation and function, the role played by the proto-oncogene c-Maf remains poorly characterized. We report herein that selective loss of c-Maf expression in the T cell compartment results in defective development of Tfh cells in response to both antigen/adjuvant vaccinations and commensal intestinal bacteria. Accordingly, c-Maf expression in T cells was essential for the development and high-affinity antibody secretion in vaccinated animals. c-Maf was expressed early, concomitantly to BCL6, in Tfh cell precursors and found to regulate Tfh fate in a cell-autonomous fashion. Altogether, our findings reveal a novel, non-redundant, function for c-Maf in the differentiation of Tfh cells and the regulation of humoral immune responses to T-cell-dependent antigens.

Tcf1 at the crossroads of CD4+ and CD8+ T cell identity

Transcription factors and DNA/histone modification enzymes work in concert to establish and maintain cell identity. CD4+ and CD8+ T cells are key players in cellular immunity with distinct functions. Recent studies offer novel insights into how their identities are established in the thymus and maintained in the periphery during immune responses. During thymic maturation, Thpok, HDAC1 and HDAC2 guard CD4+ T cells from activation of CD8+ cytotoxic genes, and Tcf1 and Lef1 utilize their intrinsic HDAC activity to shut down CD4+ lineage-associated genes in CD8+ T cells. In activated CD4+ T cells, Tcf1 and Lef1 act upstream of the Bcl6-Blimp1 axis to direct differentiation of follicular helper T (Tfh) cells, and prevent diversion of Tfh to IL-17-producing cells. In parallel, T-bet, together with Eomes or Blimp1, ensures proper induction of the cytotoxic program in CD8+ effectors elicited by acute infection, and prevents generation of pathogenic, IL-17-producing CD8+ effector T cells. Antigen persistence due to chronic viral infection leads to CD8+ T cell exhaustion. A portion of exhausted CD8+ T cells has the capacity to activate the Tfh program in a Tcf1-dependent manner. Those Tfh-like CD8+ Tcells exhibit enhanced proliferative capacity in response to PD-1 blockage therapy and are more effective in curtailing viral replication. Thus, dissecting the molecular aspects of T cell identity, during development and immune responses, may lead to new therapies for treating autoimmunity, tumors, and persistent infections.