ADAM10-Mediated ICOS Ligand Shedding on B Cells Is Necessary for Proper T Cell ICOS Regulation and T Follicular Helper Responses

Gammaherpesviruses are ubiquitous pathogens that establish life-long infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We showed that global expression of the antiviral and tumor-suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts expansion of the latent viral reservoir. In this study we found that T cell intrinsic IRF-1 expression recapitulates some aspects of antiviral state imposed by IRF-1 during chronic MHV68 infection, including attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to unhindered rise of IL-17A-expressing and follicular helper T cell populations, two CD4 + T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4 + T cell subsets that support chronic gammaherpesvirus infection. Importance Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, though exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4 + T follicular helper population. Further, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.

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Antigen-presenting ILC3 regulate T cell–dependent IgA responses to colonic mucosal bacteria

Journal of Experimental Medicine ◽

10.1084/jem.20180871 ◽

2019 ◽

Vol 216 (4) ◽

pp. 728-742 ◽

Cited By ~ 38

Author(s):

Felipe Melo-Gonzalez ◽

Hana Kammoun ◽

Elza Evren ◽

Emma E. Dutton ◽

Markella Papadopoulou ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Antigen Presentation ◽

Immunoglobulin A ◽

Lymphoid Cells ◽

Host Interactions ◽

Commensal Microbiota ◽

Follicular Helper ◽

Cell Class ◽

Antigen Presenting

Intestinal immune homeostasis is dependent upon tightly regulated and dynamic host interactions with the commensal microbiota. Immunoglobulin A (IgA) produced by mucosal B cells dictates the composition of commensal bacteria residing within the intestine. While emerging evidence suggests the majority of IgA is produced innately and may be polyreactive, mucosal-dwelling species can also elicit IgA via T cell–dependent mechanisms. However, the mechanisms that modulate the magnitude and quality of T cell–dependent IgA responses remain incompletely understood. Here we demonstrate that group 3 innate lymphoid cells (ILC3) regulate steady state interactions between T follicular helper cells (TfH) and B cells to limit mucosal IgA responses. ILC3 used conserved migratory cues to establish residence within the interfollicular regions of the intestinal draining lymph nodes, where they act to limit TfH responses and B cell class switching through antigen presentation. The absence of ILC3-intrinsic antigen presentation resulted in increased and selective IgA coating of bacteria residing within the colonic mucosa. Together these findings implicate lymph node resident, antigen-presenting ILC3 as a critical regulatory checkpoint in the generation of T cell–dependent colonic IgA and suggest ILC3 act to maintain tissue homeostasis and mutualism with the mucosal-dwelling commensal microbiota.

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Rapid Emergence of T Follicular Helper and Germinal Center B Cells Following Antiretroviral Therapy in Advanced HIV Disease

Frontiers in Immunology ◽

10.3389/fimmu.2021.752782 ◽

2021 ◽

Vol 12 ◽

Author(s):

Chun-Shu Wong ◽

Clarisa M. Buckner ◽

Silvia Lucena Lage ◽

Luxin Pei ◽

Felipe L. Assis ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Antiretroviral Therapy ◽

B Cell ◽

Germinal Center ◽

Cell Receptor ◽

B Cell Receptor ◽

Cd4 T Cell ◽

Follicular Helper ◽

Cell Counts

Low nadir CD4 T-cell counts in HIV+ patients are associated with high morbidity and mortality and lasting immune dysfunction, even after antiretroviral therapy (ART). The early events of immune recovery of T cells and B cells in severely lymphopenic HIV+ patients have not been fully characterized. In a cohort of lymphopenic (CD4 T-cell count < 100/µL) HIV+ patients, we studied mononuclear cells isolated from peripheral blood (PB) and lymph nodes (LN) pre-ART (n = 40) and 6-8 weeks post-ART (n = 30) with evaluation of cellular immunophenotypes; histology on LN sections; functionality of circulating T follicular helper (cTfh) cells; transcriptional and B-cell receptor profile on unfractionated LN and PB samples; and plasma biomarker measurements. A group of 19 healthy controls (HC, n = 19) was used as a comparator. T-cell and B-cell lymphopenia was present in PB pre-ART in HIV+ patients. CD4:CD8 and CD4 T- and B-cell PB subsets partly normalized compared to HC post-ART as viral load decreased. Strikingly in LN, ART led to a rapid decrease in interferon signaling pathways and an increase in Tfh, germinal center and IgD-CD27- B cells, consistent with histological findings of post-ART follicular hyperplasia. However, there was evidence of cTfh cells with decreased helper capacity and of limited B-cell receptor diversification post-ART. In conclusion, we found early signs of immune reconstitution, evidenced by a surge in LN germinal center cells, albeit limited in functionality, in HIV+ patients who initiate ART late in disease.

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Recombinant Rabies Virus Overexpressing OX40-Ligand Enhances Humoral Immune Responses by Increasing T Follicular Helper Cells and Germinal Center B Cells

Vaccines ◽

10.3390/vaccines8010144 ◽

2020 ◽

Vol 8 (1) ◽

pp. 144 ◽

Cited By ~ 1

Author(s):

Yingying Li ◽

Ling Zhao ◽

Baokui Sui ◽

Zhaochen Luo ◽

Yachun Zhang ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Immune Responses ◽

Rabies Virus ◽

Germinal Center ◽

Rabies Vaccine ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Follicular Helper ◽

Ox40 Ligand

Rabies, caused by the rabies virus (RABV), remains a serious threat to public health in most countries. Development of a single-dose and efficacious rabies vaccine is the most important method to restrict rabies virus transmission. Costimulatory factor OX40-ligand (OX40L) plays a crucial role in the T cell-dependent humoral immune responses through T-B cell interaction. In this work, a recombinant RABV overexpressing mouse OX40L (LBNSE-OX40L) was constructed, and its effects on immunogenicity were evaluated in a mouse model. LBNSE-OX40L-immunized mice generated a larger number of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs) than the parent virus LBNSE-immunized mice. Furthermore, LBNSE-OX40L induced significantly higher levels of virus-neutralizing antibodies (VNA) as early as seven days post immunization (dpi), which lasted for eight weeks, resulting in better protection for mice than LBNSE (a live-attenuated rabies vaccine strain). Taken together, our data in this study suggest that OX40L can be a novel and potential adjuvant to improve the induction of protective antibody responses post RABV immunization by triggering T cell-dependent humoral immune responses, and that LBNSE-OX40L can be developed as an efficacious and nonpathogenic vaccine for animals.

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B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells

Journal of Experimental Medicine ◽

10.1084/jem.20102065 ◽

2011 ◽

Vol 208 (7) ◽

pp. 1377-1388 ◽

Cited By ~ 164

Author(s):

Sau K. Lee ◽

Robert J. Rigby ◽

Dimitra Zotos ◽

Louis M. Tsai ◽

Shimpei Kawamoto ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Plasma Cells ◽

Antibody Responses ◽

B Cell Differentiation ◽

Tfh Cells ◽

Follicular Helper ◽

Microbial Infections

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell–expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6+ T cells appear at the T–B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6+ PD-1hi T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6+ T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.

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EPEN-23. A COMPUTATIONAL ANALYSIS OF THE TUMOUR IMMUNE MICROENVIRONMENT IN PAEDIATRIC EPENDYMOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa222.160 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii312-iii312

Author(s):

Timothy Ritzmann ◽

Anbarasu Lourdusamy ◽

Andrew Jackson ◽

Lisa Storer ◽

Andrew Donson ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

B Cells ◽

Computational Analysis ◽

Immune Cell ◽

Cell Populations ◽

Immune Microenvironment ◽

Tumour Immunity ◽

Follicular Helper

Abstract Ependymoma is the third commonest childhood brain tumour. Relapse is frequent, often fatal and current therapeutic strategies are inadequate. Previous ependymoma research describes an immunosuppressive environment with T-cell exhaustion, indicating a lack of response to T-cell directed immunotherapy. Understanding the immune microenvironment is therefore critical. We present a computational analysis of ependymoma, gene expression derived, immune profiles. Using 465 ependymoma samples from gene expression datasets (GSE64415, GSE50385, GSE100240) and two RNA-seq databases from UK ependymomas, we applied bulk tumour deconvolution methods (CIBERSORT and xCell) to infer immune cell populations. Additionally, we measured checkpoint blockade related mRNAs and used immunohistochemistry to investigate cell populations in ependymoma sections. CIBERSORT indicated high proportions of M2-like macrophages and smaller proportions of activated natural killer (NK) cells, T follicular helper cells, CD4+ memory T-cells and B-cells. xCell overlapped with the M2-like macrophage and CD4+ memory T-cell signatures seen in CIBERSORT. On immunohistochemistry, T and B cells were scarce, with small numbers of CD8+, CD4+ and CD20+ cells in the parenchyma but greater numbers in surrounding regions. CD68 was more highly expressed in the parenchyma. Analysis of nine checkpoint ligands and receptors demonstrated only the TIM3/GAL9 combination was reliably detectable. GAL9 is implicated in tumour interactions with T-cells and macrophages elsewhere, possibly contributing to poorer outcomes. Our study supports the presence of myeloid cells being leading contributors to the ependymoma immune microenvironment. Further work will delineate the extent of myeloid contribution to immunosuppression across molecular subtypes. Modulation of tumour immunity may contribute to better clinical outcomes.

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Atypical B cells upregulate co-stimulatory molecules during malaria and secrete antibodies with T follicular helper cell support

10.1101/2021.12.07.471601 ◽

2021 ◽

Author(s):

Christine S. Hopp ◽

Jeff Skinner ◽

Sarah L. Anzick ◽

Christopher M. Tipton ◽

Mary E. Peterson ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

Somatic Hypermutation ◽

Acute Infection ◽

Cell Receptor ◽

Tfh Cells ◽

Influenza Hemagglutinin ◽

Follicular Helper ◽

T Cell Help

ABSTRACTSeveral infectious and autoimmune diseases are associated with an expansion of CD21-CD27- atypical B cells (atBCs). The function of atBCs remains unclear and few studies have investigated the biology of pathogen-specific atBCs during acute infection. Here, we performed longitudinal RNA-sequencing and flow cytometry analyses of Plasmodium falciparum (Pf)-specific B cells before and shortly after febrile malaria, with simultaneous analysis of influenza hemagglutinin (HA)-specific B cells as a comparator. B cell receptor-sequencing showed that Pf-specific atBCs, activated B cells (actBCs) and classical memory B cells share clonality and have comparable somatic hypermutation. In response to malaria, Pf-specific atBCs and actBCs expanded and upregulated molecules that mediate B-T cell interactions, suggesting that atBCs respond to T follicular helper (Tfh) cells. Indeed, in the presence of Tfh cells and Staphylococcal enterotoxin B, atBCs of malaria-exposed individuals differentiated into CD38+ antibody-secreting cells in vitro, suggesting that atBCs may actively contribute to humoral immunity to infectious pathogens.One Sentence SummaryThis study shows that atypical B cells actively respond to acute malaria and have the capacity to produce antibodies with T cell help.

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Alterations of circulating B cells and follicular helper T cell subsets with low Ig M level in active non-segmental vitiligo

10.22541/au.159292629.93468343 ◽

2020 ◽

Author(s):

Yu Zhen ◽

Lei Yao ◽

Jianjiao Zu ◽

Siyao Zuo ◽

Shanshan Li

Keyword(s):

T Cell ◽

B Cells ◽

T Cell Subsets ◽

Helper T Cell ◽

Follicular Helper ◽

Follicular Helper T Cell

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Neoantigen driven B cell and CD4+ T follicular helper cell collaboration promotes robust anti-tumor CD8+ T cell responses

10.1101/2020.12.23.424168 ◽

2020 ◽

Author(s):

Can Cui ◽

Jiawei Wang ◽

Ping-Min Chen ◽

Kelli A. Connolly ◽

Martina Damo ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Cell ◽

Cell Interactions ◽

Tumor Control ◽

Cell Responses ◽

Tfh Cells ◽

Follicular Helper ◽

T Follicular Helper Cell

AbstractCD4+ T follicular helper (TFH) cells provide help to B cells, which is critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found TFH cells correlated with GC B cells and with prolonged survival of lung adenocarcinoma (LUAD) patients. To investigate further, we developed an LUAD model, in which tumor cells expressed B-cell- and T-cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells were necessary for tumor control, as were effector CD8+ T cells. The latter were reduced in the absence of T cell-B cell interactions or the IL-21 receptor. IL-21 was produced primarily by TFH cells, development of which required B cells. Moreover, development of tumor-specific TFH cell-responses was also reliant upon tumors that expressed B-cell-recognized neoantigens. Thus, tumor-neoantigens themselves can control the fate decisions of tumor-specific CD4+ T cells by facilitating interactions with tumor-specific B cells.Abstract Figure

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Costimulation Through GITR Increases Follicular Helper T Cell Formation and Leads To Control Of A Chronic Viral Infection

Blood ◽

10.1182/blood.v122.21.3496.3496 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3496-3496

Author(s):

Fernanda M Pascutti ◽

Tomasz Poplonski ◽

René A.W. Van Lier ◽

Claudia Brandao ◽

Martijn A. Nolte

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Cd4 T Cells ◽

Viral Infections ◽

Conflicts Of Interest ◽

Cell Formation ◽

Absolute Number ◽

Costimulatory Receptor ◽

Follicular Helper

Abstract The glucocorticoid-induced TNF receptor family-related protein (GITR) is an important costimulatory receptor on T cells. We have previously shown that enhanced costimulation through GITR increases the formation of both effector and regulatory CD4+ T cells. Here we explored whether it could also affect humoral immunity and T cell help to B cells. Although development of mature B cells was not affected in GITRL transgenic (tg) mice, we found that the number of follicular helper T cells (CXCR5+ PD1+ CD4+ T cells, Tfh) was significantly increased, including the absolute number of Tfh-B cell conjugates, as revealed by ImageStream analysis. Tfh from GITRL tg mice had normal expression levels of ICOS, SLAM and CD44 and slightly lower levels of CD62L and CCR7 compared to wild-type (WT) littermates. Interestingly, Tfh from GITRL tg mice produced more IFN-g and IL-10, which was accompanied by a biased antibody repertoire (decreased IgG3 and increased IgA, IgG2a and IgG2b). Since Tfh have been implicated in the late control of viral replication, we infected WT and GITRL tg mice with LCMV Clone 13. Surprisingly, at day 30 after infection, we could not detect viral genome in spleen and liver from GITRL tg mice, while WT mice were still infected. Also, PD-1 expression was strongly decreased on virus-specific CD8+ T cells, which correlated with faster viral clearance. All in all, these results indicate that GITR-mediated costimulation enhances the control of chronic viral infections, by boosting and modulating Tfh cell responses. Disclosures: No relevant conflicts of interest to declare.

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