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T resident helper cells promote humoral responses in the lung.

ABSTRACT: Influenza is a deadly and costly infectious disease, even during flu seasons when an effective vaccine has been developed. To improve vaccines against respiratory viruses, a better understanding of the immune response at the site of infection is crucial. After influenza infection, clonally expanded T cells take up permanent residence in the lung, poised to rapidly respond to subsequent infection. Here, we characterized the dynamics and transcriptional regulation of lung-resident CD4⁺ T cells during influenza infection and identified a long-lived, Bcl6-dependent population that we have termed T resident helper (T_RH) cells. T_RH cells arise in the lung independently of lymph node T follicular helper cells but are dependent on B cells, with which they tightly colocalize in inducible bronchus-associated lymphoid tissue (iBALT). Deletion of Bcl6 in CD4⁺ T cells before heterotypic challenge infection resulted in redistribution of CD4⁺ T cells outside of iBALT areas and impaired local antibody production. These results highlight iBALT as a homeostatic niche for T_RH cells and advocate for vaccination strategies that induce T_RH cells in the lung.

SUBMITTER: Swarnalekha N

PROVIDER: S-EPMC8063390 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Skin dendritic cells induce follicular helper T cells and protective humoral immune responses.

Project description:BACKGROUND:The contribution of individual subsets of dendritic cells (DCs) to generation of adaptive immunity is central to understanding immune homeostasis and protective immune responses. OBJECTIVE:We sought to define functions for steady-state skin DCs. METHODS:We present an approach in which we restrict antigen presentation to individual DC subsets in the skin and monitor the effects on endogenous antigen-specific CD4(+) T- and B-cell responses. RESULTS:Presentation of foreign antigen by Langerhans cells (LC) in the absence of exogenous adjuvant led to a large expansion of T follicular helper (TFH) cells. This was accompanied by B-cell activation, germinal center formation, and protective antibody responses against influenza. The expansion of TFH cells and antibody responses could be elicited by both systemic and topical skin immunization. TFH cell induction was not restricted to LCs and occurred in response to antigen presentation by CD103(+) dermal DCs. CD103(+) DCs, despite inducing similar TFH responses as LCs, were less efficient in induction of germinal center B cells and humoral immune responses. We also found that skin DCs are sufficient to expand CXCR5(+) TFH cells through an IL-6- and IFN-?/? receptor-independent mechanism, but B cells were required for sustained Bcl-6(+) expression. CONCLUSIONS:These data demonstrate that a major unappreciated function of skin DCs is their promotion of TFH cells and humoral immune responses that potentially represent an efficient approach for vaccination.

| S-EPMC4639468 | biostudies-literature

Skin-resident murine dendritic cell subsets promote distinct and opposing antigen-specific T helper cell responses.

Project description:Skin-resident dendritic cells (DCs) are well positioned to encounter cutaneous pathogens and are required for the initiation of adaptive immune responses. There are at least three subsets of skin DC- Langerhans cells (LC), Langerin(+) dermal DCs (dDCs), and classic dDCs. Whether these subsets have distinct or redundant function in vivo is poorly understood. Using a Candida albicans skin infection model, we have shown that direct presentation of antigen by LC is necessary and sufficient for the generation of antigen-specific T helper-17 (Th17) cells but not for the generation of cytotoxic lymphocytes (CTLs). In contrast, Langerin(+) dDCs are required for the generation of antigen specific CTL and Th1 cells. Langerin(+) dDCs also inhibited the ability of LCs and classic DCs to promote Th17 cell responses. This work demonstrates that skin-resident DC subsets promote distinct and opposing antigen-specific responses.

| S-EPMC3163010 | biostudies-literature

Characterization of lung tissue-resident helper T cells

Project description:To identify the characters of tissue resident CD4 T cells following influenza virus infection, we sorted lung CD45iv-CD4+CD44hi T cells from influenza PR8 infected mice (28 d.p.i.). Then the cells were performed single cell RNA sequencing. At the result, we found clera 5 differnt clusters and each cluster represent different helper T cell types including TH1, TH17 and Treg. One cluster exhibited both tissue residency and TFH cell features. So, we identify the characters of this hybrid lung CD4 T cells.

2020-11-27 | GSE153422 | GEO

Targeting T Follicular Helper Cells to Control Humoral Allogeneic Immunity.

Project description:Humoral allogeneic immunity driven by anti-HLA donor-specific antibodies and antibody-mediated rejection (AMR) significantly impede prolonged survival of organ allografts after transplantation. Although the importance of T follicular helper (TFH) cells in controlling antibody responses has been long established, their role in directing donor-specific antibody generation leading to AMR was only recently appreciated in the clinical setting of organ transplantation. In this review, we provide a comprehensive summary of the current knowledge on the biology of human TFH cells as well as their circulating counterparts and describe their pivotal role in driving humoral alloimmunity. In addition, we discuss the intrinsic effects of current induction therapies and maintenance immunosuppressive drugs as well as of biotherapies on TFH cells and provide future directions and novel opportunities of biotherapeutic targeting of TFH cells that have the potential of bringing the prophylactic and curative treatments of AMR toward personalized and precision medicine.

| S-EPMC8484368 | biostudies-literature

Tissue-resident CD4+ T helper cells assist the development of protective respiratory B and CD8+ T cell memory responses.

Project description:Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.

| S-EPMC8056937 | biostudies-literature

Characterization of lung tissue-resident helper T cells

Project description:Characterization of lung tissue-resident helper T cells

| PRJNA642631 | ENA

Bob1 maintains T follicular helper cells for long-term humoral immunity.

Project description:Humoral immunity is vital for host protection, yet aberrant antibody responses can trigger harmful inflammation and immune-related disorders. T follicular helper (Tfh) cells, central to humoral immunity, have garnered significant attention for unraveling immune mechanisms. This study shows the role of B-cell Oct-binding protein 1 (Bob1), a transcriptional coactivator, in Tfh cell regulation. Our investigation, utilizing conditional Bob1-deficient mice, suggests that Bob1 plays a critical role in modulating inducible T-cell costimulator expression and cellular respiration in Tfh cells. This regulation maintains the long-term functionality of Tfh cells, enabling their reactivation from central memory T cells to produce antibodies during recall responses. In a bronchial asthma model induced by house dust mite (HDM) inhalation, Bob1 is observed to enhance HDM-specific antibodies, including IgE, highlighting its pivotal function in Tfh cell regulation. Further exploration of Bob1-dependent mechanisms in Tfh cells holds promise for governing protective immunity and addressing immune-related disorders.

| S-EPMC10869348 | biostudies-literature

Proatherogenic conditions promote autoimmune T helper 17 cell responses in vivo.

Project description:Patients with systemic autoimmune diseases show increased incidence of atherosclerosis. However, the contribution of proatherogenic factors to autoimmunity remains unclear. We found that atherogenic mice (herein referred to as LDb mice) exhibited increased serum interleukin-17, which was associated with increased numbers of T helper 17 (Th17) cells in secondary lymphoid organs. The environment within LDb mice was substantially favorable for Th17 cell polarization of autoreactive T cells during homeostatic proliferation, which was considerably inhibited by antibodies directed against oxidized low-density lipoprotein (oxLDL). Moreover, the uptake of oxLDL induced dendritic-cell-mediated Th17 cell polarization by triggering IL-6 production in a process dependent on TLR4, CD36, and MyD88. Furthermore, self-reactive CD4(+) T cells that expanded in the presence of oxLDL induced more profound experimental autoimmune encephalomyelitis. These findings demonstrate that proatherogenic factors promote the polarization and inflammatory function of autoimmune Th17 cells, which could be critical for the pathogenesis of atherosclerosis and other related autoimmune diseases.

| S-EPMC3955722 | biostudies-literature

PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21.

Project description:Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here, we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hiCXCR5-CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hiCXCR5-CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not T follicular helper (Tfh) cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hiCD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in the kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells as a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

| S-EPMC6824311 | biostudies-literature

Enhancing humoral responses to a malaria antigen with nanoparticle vaccines that expand Tfh cells and promote germinal center induction.

Project description:For subunit vaccines, adjuvants play a key role in shaping immunological memory. Nanoparticle (NP) delivery systems for antigens and/or molecular danger signals are promising adjuvants capable of promoting both cellular and humoral immune responses, but in most cases the mechanisms of action of these materials are poorly understood. Here, we studied the immune response elicited by NPs composed of multilamellar "stapled" lipid vesicles carrying a recombinant Plasmodium vivax circumsporozoite antigen, VMP001, both entrapped in the aqueous core and anchored to the lipid bilayer surfaces. Immunization with these particles and monophosphoryl lipid A (MPLA), a US Food and Drug Administration-approved immunostimulatory agonist for Toll-like receptor-4, promoted high-titer, high-avidity antibody responses against VMP001, lasting more than 1 y in mice at 10-fold lower doses than conventional adjuvants. Compared to soluble VMP001 mixed with MPLA, VMP001-NPs promoted broader humoral responses, targeting multiple epitopes of the protein and a more balanced Th1/Th2 cytokine profile from antigen-specific T cells. To begin to understand the underlying mechanisms, we examined components of the B-cell response and found that NPs promoted robust germinal center (GC) formation at low doses of antigen where no GC induction occurred with soluble protein immunization, and that GCs nucleated near depots of NPs accumulating in the draining lymph nodes over time. In parallel, NP vaccination enhanced the expansion of antigen-specific follicular helper T cells (T(fh)), compared to vaccinations with soluble VMP001 or alum. Thus, NP vaccines may be a promising strategy to enhance the durability, breadth, and potency of humoral immunity by enhancing key elements of the B-cell response.

| S-EPMC3268296 | biostudies-other

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