Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE165250 | GEO | 2021/05/12
REPOSITORIES: GEO
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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
Project description:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity. RNA was prepared from subconfluent asynchronously proliferating cells using TRIZOL and purified by RNeasy MinElute Cleanup kit (Qiagen). Hybridization to Affymetrix GeneChip Mouse Genome 430 2.0 arrays was used to generate gene expression profiles of WT Tfh-like and SAP-deficient Tfh-like cells.
2011-12-06 | E-GEOD-32624 | biostudies-arrayexpress
Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. This SuperSeries is composed of the following subset Series: GSE21379: Expression Data from WT and Sh2d1a-/- in vivo follicular helper CD4 T cells (TFH) versus non follicular helper CD4 T cells (non-TFH) GSE21380: Expression Data from in vivo Tfh vs GC Tfh vs non-Tfh Refer to individual Series
2010-04-28 | E-GEOD-21381 | biostudies-arrayexpress
Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo polyclonal GC Tfh vs Tfh vs Non-Tfh eight days after LCMV viral infection. Analysis of in vivo follicular helper CD4 T cells (CXCR5high GL7low), versus germinal center follicular helper CD4 T cells (CXCR5hi GL7hi), versus non-follicular helper CD4 T cells (CXCR5low) eight days after viral infection.
2010-04-28 | E-GEOD-21380 | biostudies-arrayexpress
Project description:A range of current candidate AIDS vaccine regimens are focused on generating protective HIV neutralizing antibody responses. Many of these efforts rely on the rhesus macaque animal model. Understanding how protective antibody responses develop and how to increase their efficacy are both major knowledge gaps. Germinal centers (GC) are the engines of antibody affinity maturation. GC T follicular helper (GC Tfh) CD4 T cells are required for GCs. Studying vaccine-specific GC Tfh cells after protein immunizations has been challenging, as antigen-specific GC Tfh cells are difficult to identify by conventional intracellular cytokine staining (ICS). Cytokine production by GC Tfh cells may be intrinsically limited in comparison to other T helper effector cells, as the biological role of a GC Tfh cell is to provide help to individual B cells within the GC, rather than secreting large amounts of cytokines bathing a tissue. To test this idea, we developed a cytokine-independent method to identify antigen-specific GC Tfh cells. RNAseq was performed using TCR stimulated GC Tfh cells to identify candidate markers based on differentially expressed genes and other criteria. Validation experiments determined CD25 (IL2Ra) and OX40 to be highly upregulated activation induced markers on the surface of GC Tfh cells after stimulation. In comparison to ICS, the activation induced marker (AIM) assay identified > 10-fold more antigen-specific GC Tfh cells in HIV Env protein immunized macaques (BG505 SOSIP). Additionally, the AIM assay detected antigen-specific CXCR5+ and CXCR5- CD4 T cells in peripheral blood. Thus, AIM demonstrates that antigen-specific GC Tfh cells are intrinsically stingy producers of cytokines, which is likely an essential part of their biological function. Total RNA obtained from GC Tfh cells from 3 rhesus macaque lymph node cell samples stimulated with Staphylococcal Enterotoxin B compared with 2 unstimulated cell samples.
2016-09-07 | E-GEOD-81382 | biostudies-arrayexpress
Project description:CD4 T cell help is critical for both the generation and maintenance of germinal centers, and T follicular helper (TFH) cells are the CD4 T cell subset required for this process. SAP (SH2D1A) expression in CD4 T cells is essential for germinal center development. However, SAP-deficient mice have only a moderate defect in TFH differentiation as defined by common TFH surface markers. CXCR5+ TFH cells are found within the germinal center as well as along the boundary regions of T/B cell zones. Here we show that germinal center associated T cells (GC TFH) can be identified by their co-expression of CXCR5 and the GL7 epitope, allowing for phenotypic and functional analysis of TFH and GC TFH populations. Here we show GC TFH are a functionally discrete subset of further polarized TFH cells, with enhanced B cell help capacity and a specialized ability to produce IL-4 in a TH2-independent manner. Strikingly, SAP-deficient mice have an absence of the GC TFH subset and SAP- TFH are defective in IL-4 and IL-21 production. We further demonstrate that SLAM (Slamf1, CD150), a surface receptor that utilizes SAP signaling, is specifically required for IL-4 production by GC TFH. GC TFH cells require IL-4 and IL-21 production for optimal help to B cells. These data illustrate complexities of SAP-dependent SLAM family receptor signaling, revealing a prominent role for SLAM receptor ligation in IL-4 production by germinal center CD4 T cells but not in TFH and GC TFH differentiation. Analysis of in vivo antigen-specific (LCMV-specific, SMARTA TCR transgenic) WT and Sh2d1a-/- follicular helper CD4 T cells (CXCR5high),versus non-follicular helper CD4 T cells (CXCR5low), eight days after viral infection.
2010-04-28 | E-GEOD-21379 | biostudies-arrayexpress
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:Follicular T helper cells (Tfh) are critical for providing help to B cells for germinal center (GC) formation. Mutations affecting SAP prevent GC formation due to defective T:B cell interactions, yet effects on Tfh cell differentiation remain unclear. We describe the in vitro differentiation of functionally competent “Tfh-like” cells that expressed IL-21, Tfh markers, and Bcl6, and rescued GC formation in SAP-deficient hosts substantially better than other T helper (Th) cells. SAP-deficient Tfh-like cells appeared virtually indistinguishable from wildtype, yet failed to support GCs in vivo. Interestingly, both Tfh-like and in vivo-derived Tfh cells could produce effector cytokines in response to polarizing conditions. Moreover, other Th cell populations could be reprogrammed to obtain Tfh characteristics. ChIP-Seq analyses revealed positive epigenetic markings on Tbx21, Gata3 and Rorc in Tfh-like and ex vivo Tfh cells, and Bcl6 in other Th cells, supporting the concept of plasticity between Tfh and other Th populations. We describe the in vitro differentiation of functionally competent IL-21-producing cells with Tfh-like properties. Importantly, transfer of low numbers of these cells induced GC formation in SAP-deficient hosts more effectively than other in vitro differentiated Th cells, suggesting they represent bona fide Tfh cell precursors. We have chosen the name “Tfh-like” cells for these in vitro differentiated IL-21 producing cells as they exhibit Tfh characteristics, but do not reside within B cell follicles. SAP-deficient Tfh-like cells were virtually indistinguishable from WT, yet nonetheless, failed to effectively contribute to Tfh cells and rescue GC formation in vivo. Evaluation of cytokine production as well as epigenetic chromatin modifications of genes encoding Th cell-specific transcription factors from either in vitro-generated Tfh-like cells or Tfh cells isolated directly ex vivo provided evidence for plasticity between Tfh-like and other Th cell populations. Our results provide insight into the requirements for differentiation and plasticity of Tfh cells, which are critical for the generation of effective long-term humoral immunity.
2011-12-06 | GSE32624 | GEO
Project description:In patient serum, HBsAg particles can outnumber HBV particles by 1000:1 or higher. To explore the interactions between HBsAg and hepatocytes, concentrating on the possible effects of persistently secreting HBsAg on the functions of host cells, we have used the S gene of a full-length HBV isolate derived from an HBsAg chronic carrier (code No. C8, GenBank accession No. AF461363), cloned into pCMV vector to transfect HepG2 cells. G418 resistant clones secreting HBsAg were selected to establish permanent cell lines, and control clones transfected only with the vector were passaged as well to serve as controls. Cells were separately collected on the fourth and the eighth day after seeding, and gene expression profiles of both cell clones were studied and compared by microarray. Totally, 340 genes were suppressed and 673 genes were induced by the expression of HBsAg on the fourth day, whereas 219 genes were down-regulated and 683 genes were up-regulated on the eighth day. Arbitrarily, changes of genes detected on both 4th and 8th day cultures were selected for further study. Many cellular functions such as immune response, xenobiotic metabolism, ubiquitin pathway, transcription regulation were affected by HBsAg expression, indicating a close association between HBsAg and host cells. Experiment Overall Design: HBsAg particles are composed of viral envelope proteins and outnumber HBV virions by 1000:1 or even higher. This unique characteristic of HBV remains to be one of the challenges in basic and clinical aspects of viral hepatitis B. Experiment Overall Design: In this study, we want to explore the interactions between HBsAg and hepatocytes, concentrating on the effects of persistently secreting HBsAg on host cell functions.
2008-06-13 | E-GEOD-4549 | biostudies-arrayexpress