PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal flu vaccine
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA743946 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Anti-PD-1 (aPD1) immunotherapy likely affects other immune cells including follicular helper CD4 T cells (Tfh) involved in germinal center (GC) responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on non-cancer immune responses in humans. To investigate this question, we examined the impact of aPD1 immunotherapy for cancer on the Tfh-B cell axis responding to unrelated viral antigens. Following influenza vaccination, a subset of adults receiving aPD1 had more robust circulating Tfh (cTfh) responses than adults not receiving immunotherapy, and cTfh responses correlated with plasmablasts. PD-1 pathway blockade also resulted in transcriptional signatures of increased cellular proliferation in cTfh and responding B cells compared to controls.
2022-06-01 | GSE179487 | GEO
Project description:Cytidine diphosphate (CDP)-ethanolamine pathway of phospholipid metabolism coordinates metabolic programming of Tfh cell responses and humoral immunity.
2021-05-26 | GSE147190 | GEO
Project description:Metabolic control of Tfh and humoral immunity by phosphatidylethanolamine
| PRJNA613290 | ENA
Project description:Generating durable humoral immunity through vaccination depends upon effective interaction of follicular helper T cells (Tfh) with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing co-stimulatory and cytokine-dependent Tfh help to B cells. However, the question remains whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced anti-Envelope (Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein (IP)-10-adjuvanted HIV-1 DNA prime, followed by an MPLA+QS-21-adjuvanted Env protein boost in macaques (DIP-10 PALFQ), we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity to V1V2, and effector functions when compared to macaques primed with DNA lacking IP-10 and boosted with MPLA+alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibodies in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody response.
2019-12-10 | GSE141707 | GEO
Project description:T follicular helper (TFH) cells promote affinity maturation of B cells in germinal centers (GCs), whereas T follicular regulatory (TFR) cells limit GC reaction. Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels mediated by STIM and ORAI proteins is a fundamental signaling pathway in T lymphocytes. Here we show that SOCE is required for the differentiation and function of both TFH and TFR cells. Conditional deletion of Stim1 and Stim2 genes in T cells or Treg cells results in spontaneous autoantibody production and humoral autoimmunity. Conversely, antibody-mediated immune responses following viral infection critically depend on SOCE in TFH cells. Mechanistically, STIM1 and STIM2 control early TFR and TFH cell differentiation through NFAT-mediated IRF4, BATF and Bcl-6 expression. SOCE plays a dual role in GC response by controlling TFH and TFR cell function, thus enabling protective B cell responses and preventing humoral autoimmunity. RNAseq analyses of WT and Stim1Stim2 DKO follicular T cells and non-follicular T cells; 4-6 mice per cohort in duplicates. Mice were infected for 10 days with LCMV.
2016-03-10 | E-GEOD-79039 | biostudies-arrayexpress
Project description:CD4+ T follicular helper (Tfh) cells are essential for germinal center (GC) and high-affinity antibody responses. Yet the regulation that determines the initial development of Tfh cells is still largely unknown. Here we find that transcription factor Foxp1, previously shown to be essential in maintaining T cell quiescence, is a rate-limiting and essential negative regulator of Tfh cell differentiation. NaM-CM-/ve CD4+ T cells constitutively express Foxp1A, and stimulation through the T cell receptor (TCR) transiently induces the expression of a shorter Foxp1D isoform. In T cell-dependent (TD) humoral responses, CD4+ T cells deficient in all Foxp1 isoforms preferentially differentiate into Tfh cells, resulting in substantially increased GC and antibody responses. This negative regulation of Foxp1 on Tfh cell differentiation shows profound dominance: even in the absence of B cells, Foxp1-deficient CD4+ T cells differentiate into Tfh cells with high frequencies and sustained Bcl6 expression. Further, in the absence of Foxp1, Tfh cells are generated in higher frequencies than seen with Bcl6 overexpression and Tfh cell differentiation becomes significantly resistant to Blimp1-mediated repression. Finally, our experiments reveal specific roles of Foxp1A and Foxp1D in inhibiting Tfh cell differentiation: TCR-induced Foxp1D functions as a M-bM-^@M-^XgatekeeperM-bM-^@M-^Y to block the initial Tfh cell development, and together Foxp1A and Foxp1D proteins inversely determine Tfh cell generation in a dosage-dependent manner. Our study suggests that two Foxp1 isoforms provide a M-bM-^@M-^\double checkM-bM-^@M-^] mechanism as fundamental regulators in Tfh cell differentiation and humoral responses. Gene expression analysis of ex vivo OT-II Foxp1-WT Tfh cells and OT-II Foxp-conditional knockout (CKO) Tfh cells 5 days after immunization.
2014-05-18 | E-GEOD-50725 | biostudies-arrayexpress
Project description:During chronic viral infection, the inflammatory function of CD4 T cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this T cell adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T cells during chronic infection. Unexpectedly, our analyses revealed an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10+IL-21+co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10+IL-21+co-producing CD4 T cells or deletion of Il10 specifically in Tfh cells resulted in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling was required for sustaining germinal center reactions. Lastly, we demonstrate that IL-27 and type I IFNs differentially regulate the formation of this protective IL-10-producing Tfh subset. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.
2018-10-29 | GSE111025 | GEO
Project description:T follicular helper (Tfh) cells are a specialized subset of CD4 T cells that are essential for most antibody productions and humoral responses. It is well characterized that transcriptional network exerts indispensable roles in Tfh cell differentiation. However, how post-transcriptional regulation controls Tfh biology has largely remained unclear. Multiple mice models were used here by a series of experimental approaches to illustrate m6A methyltransferase Mettl3 programs Tfh cell differentiation at post-transcriptional layer.
2021-01-19 | GSE129648 | GEO
Project description:T follicular helper cells (TFH) are critical for the development and maintenance of germinal centers (GC) and humoral immune responses. During chronic HIV/SIV infection TFH accumulate, possibly as a result of antigen persistence. The HIV/SIV-associated TFH expansion may also reflect lack of regulation by suppressive follicular regulatory CD4+ T-cells (TFR). TFR are natural regulatory T-cells (TREG) that migrate into the follicle and, similarly to TFH, up-regulate CXCR5, Bcl-6, and PD1. Here we identified TFR as CD4+CD25+FoxP3+CXCR5+PD1hiBcl-6+ within lymph nodes of rhesus macaques (RM) and confirmed their localization within the GC by immunohistochemistry. RNA sequencing showed that TFR exhibit a distinct transcriptional profile with shared features of both TFH and TREG, including intermediate expression of FoxP3, Bcl-6, PRDM1, IL-10, and IL-21. In healthy, SIV-uninfected RM, we observed a negative correlation between frequencies of TFR and both TFH and GC B-cells as well as levels of CD4+ T-cell proliferation. Following SIV infection, the TFR/TFH ratio was reduced with no change in the frequency of TREG or TFR within the total CD4+ T-cell pool. Finally, we examined whether higher levels of direct virus infection of TFR were responsible for their relative depletion post-SIV infection. We found that TFH, TFR and TREG sorted from SIV- infected RM harbor comparable levels of cell-associated viral DNA. Our data suggests that TFR may contribute to the regulation and proliferation of TFH and GC B-cells in vivo and that a decreased TFR/TFH ratio in chronic SIV infection may lead to unchecked expansion of both TFH and GC B-cells. TFR, TFH, TREG and bulk CD4 cells were sorted from spleens of 5 uninfected and 5 infected RM.
2015-09-02 | E-GEOD-69756 | biostudies-arrayexpress