Follicular regulatory T cells can be specific for the immunizing antigen and derive from naive T cells.

Meryem Aloulou,Michelle A Linterman,Alexandre Bignon,Edward J Carr,Mylène Gador,Roland S Liblau,Nicolas Fazilleau

doi:10.1038/ncomms10579

Meryem Aloulou, Michelle A Linterman + Show 5 more

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https://doi.org/10.1038/ncomms10579

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T follicular regulatory (Tfr) cells are a subset of Foxp3+ regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the magnitude of the response. Despite an increased interest in the role of Tfr cells in humoral immunity, many fundamental aspects of their biology remain unknown, including whether they recognize self- or foreign antigen. Here we show that Tfr cells can be specific for the immunizing antigen, irrespective of whether it is a self- or foreign antigen. We show that, in addition to developing from thymic derived Treg cells, Tfr cells can also arise from Foxp3− precursors in a PD-L1-dependent manner, if the adjuvant used is one that supports T-cell plasticity. These findings have important implications for Tfr cell biology and for improving vaccine efficacy by formulating vaccines that modify the Tfr:Tfh cell ratio.

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T follicular regulatory (Tfr) cells are a subset of Foxp[3] þ regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the magnitude of the response
We found almost no pMHCII tetramer þ CD4 þ T cells, either Foxp[3] À or Foxp[3] þ, in the inguinal and periaortic lymph nodes (LNs) of both WT and Dko mice (Fig. 1a and Supplementary Fig. 1); this is consistent with the findings of Jenkins and colleagues who demonstrated that there are B250 tetramer-binding CD4 þ T cells per mouse in the steady state[21,22]
We examined this I-Ab-restricted murine T-cell response in the draining LN after subcutaneous (s.c.) immunization with MOG35-55 emulsified in Complete Freund’s Adjuvant (CFA)

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T follicular regulatory (Tfr) cells are a subset of Foxp[3] þ regulatory T (Treg) cells that form in response to immunization or infection, which localize to the germinal centre where they control the magnitude of the response. Tfr cells were first identified in the GC of human tonsils[5] and their biology was elucidated in mice[6,7,8] These cells are thought to form after vaccination when Foxp[3] þ precursors co-opt the Tfh cell differentiation pathway, acquiring a Tfh-like phenotype that includes expression of Bcl-6, CXCR5, PD-1 and ICOS. Control of Tfr cell differentiation utilizes molecular pathways that are both common to, and distinct from, Tfh cells, including the expression of Helix–Loop–Helix proteins Id2 and Id3 to limit Tfr cell formation[9] and NFAT to facilitate CXCR5 upregulation on Foxp[3] þ T cells[10], a function of Ascl-2 in Tfh cells[11]. This research revealed that Tfr cells can derive from Treg cells that are induced in the periphery (pTreg) in addition to thymic derived Treg cells (tTreg), a process that required PD-L1 signalling

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