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

ABSTRACT: 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 up-regulation 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 up-regulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes.

SUBMITTER: Jacobsen JT

PROVIDER: S-EPMC9007630 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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

Jacobsen Johanne T JT Hu Wei W R Castro Tiago B TB Solem Sigrid S Galante Alice A Lin Zeran Z Allon Samuel J SJ Mesin Luka L Bilate Angelina M AM Schiepers Ariën A Shalek Alex K AK Rudensky Alexander Y AY Victora Gabriel D GD

Science (New York, N.Y.) 20210715 6552

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<sup> ...[more]

PMID: 34437125

Similar Datasets

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

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

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

| PRJNA724728 | ENA

T follicular helper cell dynamics in germinal centers.

Project description:T follicular helper (T(FH)) cells are a specialized subset of effector T cells that provide help to and thereby select high-affinity B cells in germinal centers (GCs). To examine the dynamic behavior of T(FH) cells in GCs in mice, we used two-photon microscopy in combination with a photoactivatable fluorescent reporter. Unlike GC B cells, which are clonally restricted, T(FH) cells distributed among all GCs in lymph nodes and continually emigrated into the follicle and neighboring GCs. Moreover, newly activated T(FH) cells invaded preexisting GCs, where they contributed to B cell selection and plasmablast differentiation. Our data suggest that the dynamic exchange of T(FH) cells between GCs ensures maximal diversification of T cell help and that their ability to enter ongoing GCs accommodates antigenic variation during the immune response.

| S-EPMC3941467 | biostudies-literature

Loss of Bcl-6-Expressing T Follicular Helper Cells and Germinal Centers in COVID-19.

Project description:Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.

| S-EPMC7437499 | biostudies-literature

Neonatal T Follicular Helper Cells Are Lodged in a Pre-T Follicular Helper Stage Favoring Innate Over Adaptive Germinal Center Responses.

Project description:T follicular helper (Tfh) cells have emerged as a critical limiting factor for controlling the magnitude of neonatal germinal center (GC) reactions and primary vaccine antibody responses. We compared the functional attributes of neonatal and adult Tfh cells at the transcriptomic level and demonstrated that the Tfh cell program is well-initiated in neonates although the Tfh gene-expression pattern (i.e., CXCR5, IL-21, BCL6, TBK1, STAT4, ASCL2, and c-MAF) is largely underrepresented as compared to adult Tfh cells. Importantly, we identified a TH2-bias of neonatal Tfh cells, with preferential differentiation toward short-lived pre-Tfh effector cells. Remarkably, adjuvantation with CpG-ODNs redirect neonatal pre-Tfh cells toward committed GC-Tfh cells, as illustrated by increased expression of Tfh signature genes and reduced expression of TH2-related genes.

| S-EPMC6700230 | biostudies-literature

DOCK8 is essential for LFA-1-dependent positioning of T follicular helper cells in germinal centers.

Project description:T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell-dependent (TD) antigens. This process requires interactions between lymphocyte function-associated antigen 1 (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 had impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they developed 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 was defective. Following T cell receptor (TCR)/CD3 ligation, DOCK8-deficient T cells had impaired LFA-1 activation and reduced binding to ICAM-1. Our results therefore indicate that DOCK8 is important for LFA-1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.

| S-EPMC7455063 | biostudies-literature

CD25(+) Bcl6(low) T follicular helper cells provide help to maturing B cells in germinal centers of human tonsil.

Project description:The majority of CXCR5(+) PD1(+) CD4(+) T follicular helper (Tfh) cells (>90%) are CD25(-) Bcl6(hi) , while a small subpopulation (<10%) are CD25(+) Bcl6(low) but do not express FoxP3 and are not T regulatory cells. We purified T:B-cell conjugates from tonsils and found they were enriched for the CD25(+) Bcl6(low) Tfh-cell subpopulation. In response to IL-2, these CD25(+) Tfh cells increased expression of costimulatory molecules ICOS or OX40, upregulated transcription factor cMaf, produced cytokines IL-21, IL-17, and IL-10, and raised the levels of antiapoptotic protein Bcl2. Conjugates formed with CD25(+) BCl6(low) Tfh cells included B cells expressing higher levels of activation-induced cytidine deaminase (AID), memory marker CD45RO, surface IgG or IgA, and MHC class II compared to B-cell conjugates including CD25(-) Bcl6(hi) Tfh cells. While IL-2 suppresses early Tfh-cell differentiation, Tfh-cell recognition of antigen-presenting B cells and signaling through the T-cell receptor likely triggers expression of the high-affinity IL-2 receptor and responses to IL-2 including downregulation of Bcl6. CD25 expression on Tfh cells and local production of IL-2 in tonsil or lymph node may support B helper T-cell function during later stages of B-cell maturation and the development of immune memory.

| S-EPMC4293275 | biostudies-literature

Continually recruited naive T cells contribute to the follicular helper and regulatory T cell pools in germinal centers.

Project description:Follicular helper T cells (TFH) mediate B cell selection and clonal expansion in germinal centers (GCs), and follicular regulatory T cells (TFR) prevent the emergence of self-reactive B cells and help to extinguish the reaction. Here we show that GC reactions continually recruit T cells from both the naïve conventional and naive thymic regulatory T cell (Treg) repertoires. In the early GC, newly recruited T cells develop into TFH, whereas cells entering during the contraction phase develop into TFR cells that contribute to GC dissolution. The TFR fate decision is associated with decreased antigen availability and is modulated by slow antigen delivery or mRNA vaccination. Thus, invasion of ongoing GCs by newly developing TFH and TFR helps remodel the GC based on antigen availability.

| S-EPMC10618265 | biostudies-literature

Foxp3+ follicular regulatory T cells control the germinal center response.

Project description:Follicular helper (T(FH)) cells provide crucial signals to germinal center B cells undergoing somatic hypermutation and selection that results in affinity maturation. Tight control of T(FH) numbers maintains self tolerance. We describe a population of Foxp3(+)Blimp-1(+)CD4(+) T cells constituting 10-25% of the CXCR5(high)PD-1(high)CD4(+) T cells found in the germinal center after immunization with protein antigens. These follicular regulatory T (T(FR)) cells share phenotypic characteristics with T(FH) and conventional Foxp3(+) regulatory T (T(reg)) cells yet are distinct from both. Similar to T(FH) cells, T(FR) cell development depends on Bcl-6, SLAM-associated protein (SAP), CD28 and B cells; however, T(FR) cells originate from thymic-derived Foxp3(+) precursors, not naive or T(FH) cells. T(FR) cells are suppressive in vitro and limit T(FH) cell and germinal center B cell numbers in vivo. In the absence of T(FR) cells, an outgrowth of non-antigen-specific B cells in germinal centers leads to fewer antigen-specific cells. Thus, the T(FH) differentiation pathway is co-opted by T(reg) cells to control the germinal center response.

| S-EPMC3182542 | biostudies-literature

Development of Tbet- and CD11c-expressing B cells in a viral infection requires T follicular helper cells outside of germinal centers.

Project description:Tbet+CD11c+ B cells arise during type 1 pathogen challenge, aging, and autoimmunity in mice and humans. Here, we examined the developmental requirements of this B cell subset. In acute infection, T follicular helper (Tfh) cells, but not Th1 cells, drove Tbet+CD11c+ B cell generation through proximal delivery of help. Tbet+CD11c+ B cells developed prior to germinal center (GC) formation, exhibiting phenotypic and transcriptional profiles distinct from GC B cells. Fate tracking revealed that most Tbet+CD11c+ B cells developed independently of GC entry and cell-intrinsic Bcl6 expression. Tbet+CD11c+ and GC B cells exhibited minimal repertoire overlap, indicating distinct developmental pathways. As the infection resolved, Tbet+CD11c+ B cells localized to the marginal zone where splenic retention depended on integrins LFA-1 and VLA-4, forming a competitive memory subset that contributed to antibody production and secondary GC seeding upon rechallenge. Therefore, Tbet+CD11c+ B cells comprise a GC-independent memory subset capable of rapid and robust recall responses.

| S-EPMC8965751 | biostudies-literature

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