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Investigating the role of DOCK8 in T follicular helper cells positioning and function in germinal centers

ABSTRACT: T follicular helper (Tfh) cell migration into germinal centers (GC) is essential for the generation of GC B cells and antibody responses to T dependent (TD) antigens. This process requires interactions between LFA-1 on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells have impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they develop normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8 deficient T cells into GCs is defective. Following TCR/CD3 ligation, DOCK8 deficient T cells have impaired LFA-1 activation and reduced binding to ICAM-1. DOCK8 is important for LFA1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.

ORGANISM(S): Mus musculus

PROVIDER: GSE154897 | GEO | 2020/07/23

REPOSITORIES: GEO

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Expression data of Tfh cells

Project description:Follicular helper T (Tfh) cells access the B cell follicle to promote antibody responses, and are particularly important for germinal center (GC) reactions. However, the molecular mechanisms of how Tfh cells are physically associated with GCs are incompletely understood. Here we report that the sphingosine-1-phosphate receptor 2 (S1PR2) gene is highly expressed in a subpopulation of Tfh cells that localizes in GCs. S1PR2-deficient Tfh cells exhibited reduced accumulation in GCs due to their impaired retention. T cells deficient in both S1PR2 and CXCR5 were ineffective in supporting GC responses compared to T cells deficient only in CXCR5. These results suggest that S1PR2 and CXCR5 cooperatively regulate localization of Tfh cells in GCs to support GC responses. Venus-high Tfh, Venus-low Tfh, PD1-intermediate Th, PD1-low Th and naïve CD4+ T cells were sorted on FACSAria from immunized S1pr2V/+ mice or control mice for RNA extraction and hybridization on Affimetrix microarrays.

2014-05-30 | E-GEOD-56883 | biostudies-arrayexpress

Expression data of Tfh cells

2014-05-30 | GSE56883 | GEO

Comparative gene expression profiles of T-dependent and T-independent germinal centre B cells in mice

2007-09-05 | GSE8906 | GEO

Transcription profiling of mouse T-dependent and T-independent germinal center B cells

Project description:Selection of B cells subjected to hypermutation in germinal centres (GC) during T-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and T-independent germinal centre B cells. We have now compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC. Experiment Overall Design: QMxB6 F1 mice were immunised with T-independent antigens (NP-Ficoll) or T-dependent antigens (NP-CGG). T-dependent responses were analysed in carrier primed mice and non-carrier primed mice. The kinetics in carrier primed mice are comparable to those of TI-2 antigens, and thus, both of these groups were analysed 4 days after immunization with soluble antigen. The response in non-carrier primed mice peaks later, and was therefore analysed on day 10 after immunization. Germinal centre B cells were MACS enriched and then FACS sorted according to GL-7 and B220 expression. Sorted B cells from the relevant mice were pooled (4-10 mice per sample). Each sample thus contains B cells from different mice, and the replicates are biological, not technical replicates.

2008-06-16 | E-GEOD-8906 | biostudies-arrayexpress

Cytokine-independent detection of antigen-specific germinal center T follicular helper (Tfh) cells in immunized non-human primates using a live cell Activation Induced Marker (AIM) technique

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

Plexin B2 and Semaphorin 4C guide T-cell recruitment and function in the germinal center

Project description:Follicular T-helper (TFH) cells are essential for germinal center (GC) responses. TFH localization in GCs is controlled by chemo-guidance cues and antigen-specific adhesion. Here we define an antigen-independent, contact-dependent, adhesive guidance system for TFH cells. Unusual for amoeboid cell migration, the system is composed of transmembrane plexin B2 (PlxnB2) molecule that is highly expressed by GC B cells and its transmembrane binding partner semaphorin 4C (Sema4C) that is upregulated on TFH cells. Instead of effectuating repulsion as a ligand, Sema4C serves as the receptor to sense PlxnB2 and bias TFH migration inward at the GC edge to penetrate the GC territory. The absence of PlxnB2 from the GC or Sema4C from TFH cells causes TFH accumulation along the GC border, impairs TFH -B cell interactions and is associated with defective plasma cell production and affinity maturation. Therefore, Sema4C and PlxnB2 regulate GC TFH recruitment and function and optimal antibody responses.

2017-06-12 | GSE96819 | GEO

Foxp1 is a rate-limiting and essential negative regulator of Tfh cell differentiation

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

Cytokine-independent detection of antigen-specific germinal center T follicular helper (Tfh) cells in immunized non-human primates using a live cell Activation Induced Marker (AIM) technique

2016-09-07 | GSE81382 | GEO

Store-operated Ca2+ entry in follicular T cells controls humoral immune responses and autoimmunity

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

Expression of Foxp3 by T follicular helper cells in end-stage germinal centers

Project description:Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to upregulation of the transcription factor Foxp3 by T follicular helper (Tfh) cells. Ectopic expression of Foxp3 in Tfh cells is sufficient to decrease GC size, implicating the natural upregulation of Foxp3 by Tfh cells as a potential regulator of GC lifetimes.

2021-07-15 | GSE173227 | GEO

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