Foxp3 follicular regulatory T cells control T follicular helper cells and the germinal center response

Cambridge Institute for Medical Research and the Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, UK.
Nature medicine (Impact Factor: 27.36). 07/2011; 17(8):975-82. DOI: 10.1038/nm.2425
Source: PubMed


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.

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    • "biotinylated CXCR5 (SPRCL5), followed by BV605-streptavidin, and biotinylated CD95, followed by BV421-streptavidin. In some experiments, cells were permeabilized using Cytofix/Cytoperm solution (BD) for staining with anti–IL-21 mAb (BL25168; BioLegend) or permeabilized with FoxP3 buffer for bcl6 (K112-91; BD) or FoxP3 (FJK-16S; eBioscience) staining according to manufacturer's instructions to confirm that adoptively transferred OT-II CD4 + T cells do not form follicular regulatory T cells (Linterman et al., 2011). Stained cells were analyzed with LSRII or FACSCalibur flow cytometer (BD). "
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    ABSTRACT: Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell-DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4(+) T cells. During inflammation, weak tetramer-binding TP-deficient CD4(+) T cells were preferentially expanded compared with TP-proficient CD4(+) T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4(+) T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4(+) T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4(+) T cell-DC interactions by TXA2-TP signaling improves the overall quality of adaptive immune responses. © 2014 Moalli et al.
    Full-text · Article · Dec 2014 · Journal of Experimental Medicine
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    • "PD1highCXCR5+CD4+cells have previously been reported which include GL7+ Tfh cells that are concentrated inside the GC and identify the most mature Tfh subset and most recently, Foxp3+ follicular regulatory (Tfr) cells., and Ki67+ proliferating Tfh [51], [59], [60]. Ki67+ proliferating Tfh cells were found to peak 5 days after SRBC immunization and then gradually decreased with time, and similar trends were noted with the other Tfh subsets (Figure S2C). "
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    ABSTRACT: Background Continuous support from follicular CD4+ T helper (Tfh) cells drives germinal center (GC) responses, which last for several weeks to produce high affinity memory B cells and plasma cells. In autoimmune Sle1 and NZB/W F1 mice, elevated numbers of Tfh cells persist, promoting the expansion of self-reactive B cells. Expansion of circulating Tfh like cells have also been described in several autoimmune diseases. Although, the signals required for Tfh differentiation have now been well described, the mechanisms that sustain the maintenance of fully differentiated Tfh are less understood. Recent data demonstrate a role for GC B cells for Tfh maintenance after protein immunization. Methods and Finding Given the pathogenic role Tfh play in autoimmune disease, we explored whether B cells are required for maintenance of autoreactive Tfh. Our data suggest that the number of mature autoreactive Tfh cells is controlled by GC B cells. Depletion of B cells in Sle1 autoimmune mice leads to a dramatic reduction in Tfh cells. In NZB/W F1 autoimmune mice, similar to the SRBC immunization model, GC B cells support the maintenance of mature Tfh, which is dependent mainly on ICOS. The CD28-associated pathway is dispensable for Tfh maintenance in SRBC immunized mice, but is required in the spontaneous NZB/W F1 model. Conclusion These data suggest that mature Tfh cells require signals from GC B cells to sustain their optimal numbers and function in both autoimmune and immunization models. Thus, immunotherapies targeting B cells in autoimmune disease may affect pathogenic Tfh cells.
    Full-text · Article · Aug 2014 · PLoS ONE
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    • "Aside from the aforementioned studies on the development of the Th1- and Th17-associated Treg cells, the differentiation of other specialized Treg cell populations has not been extensively studied. These include Bcl-6+ T “follicular regulatory” (Tfr) cells that express the B cell-associated chemokine receptor CXCR5, localize to B cell follicles and germinal centers in the secondary lymphoid tissues and regulate the magnitude and output of the germinal center response (112, 113). These Tfr cells develop in parallel to Bcl-6+ T follicular helper (Tfh) cells that promote humoral immunity, and share some of their developmental requirements such as CD28 mediated co-stimulation and signaling lymphocytic activation molecule-associated protein (SAP)-dependent interaction with B cells. "
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    ABSTRACT: Foxp3(+) regulatory T cells (Treg cells) are essential for establishing and maintaining self-tolerance, and also inhibit immune responses to innocuous environmental antigens. Imbalances and dysfunction in Treg cells lead to a variety of immune-mediated diseases, as deficits in Treg cell function contribute to the development autoimmune disease and pathological tissue damage, whereas overabundance of Treg cells can promote chronic infection and tumorigenesis. Recent studies have highlighted the fact that Treg cells themselves are a diverse collection of phenotypically and functionally specialized populations, with distinct developmental origins, antigen-specificities, tissue-tropisms, and homeostatic requirements. The signals directing the differentiation of these populations, their specificities and the mechanisms by which they combine to promote organ-specific and systemic tolerance, and how they embody the emerging property of regulatory memory are the focus of this review.
    Full-text · Article · Jul 2014 · Frontiers in Immunology
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