Regulatory roles of IL-10-producing human follicular T cells.

Pablo F Cañete,David H Canaday,Rebecca A Sweet,Ismail Sayin,Carola G Vinuesa,Emma Barry,Matthew C Cook,Angel Lopez,Ilenia Papa,Michael Meyer-Hermann,Barbara Fazekas De St Groth,Katharine J Bassett,Paula Gonzalez-Figueroa,Naganari Ohkura,Holly Bolton,Marta Cuenca,Shimon Sakaguchi,Claudio Doglioni,Jonathan A Roco

doi:10.1084/jem.20190493

Abstract

Mucosal lymphoid tissues such as human tonsil are colonized by bacteria and exposed to ingested and inhaled antigens, requiring tight regulation of immune responses. Antibody responses are regulated by follicular helper T (TFH) cells and FOXP3+ follicular regulatory T (TFR) cells. Here we describe a subset of human tonsillar follicular T cells identified by expression of TFH markers and CD25 that are the main source of follicular T (TF) cell-derived IL-10. Despite lack of FOXP3 expression, CD25+ TF cells resemble T reg cells in high CTLA4 expression, low IL-2 production, and their ability to repress T cell proliferation. CD25+ TF cell-derived IL-10 dampens induction of B cell class-switching to IgE. In children, circulating total IgE titers were inversely correlated with the frequencies of tonsil CD25+ TF cells and IL-10-producing TF cells but not with total T reg cells, TFR, or IL-10-producing T cells. Thus, CD25+ TF cells emerge as a subset with unique T and B cell regulatory activities that may help prevent atopy.

Highlights

High-affinity antibodies are critical for long-lived host defense after infection or vaccination
Identification of tonsillar CD25+ forkhead box P3 (FOXP3)− TF cells that express abundant IL-10 In an effort to identify the human equivalent of mouse TFR cells, we stained cells from the most accessible human secondary lymphoid tissue, tonsil, for markers of TF cells and T reg cells
CD25+ FOXP3− TF cells were present in human mesenteric lymph nodes, these were less frequent than those seen in the tonsil and found at proportions comparable to CD25+ FOXP3+ T cells (P = 0.2236; Fig. S1)

Summary

Introduction

High-affinity antibodies are critical for long-lived host defense after infection or vaccination. TFR cells have been shown to repress GC B cells and antibody responses (Sage et al, 2016). B cell lymphoma 6 protein (BCL6)–driven B helper follicular T (TFH) cells are essential in supporting and regulating the quality and longevity of antibody responses (Crotty, 2011; Vinuesa et al, humans (Lim et al, 2004; Carreras et al, 2006; Chung et al, 2011) and circulating follicular FOXP3+ regulatory populations have been described (Fonseca et al, 2017; Wing et al, 2017). TFH cells first interact with antigen-specific B cells at the the nature of TFR cells in human tonsil, the most borders between T cell zones and B cell follicles, driving B cells to accessible human secondary lymphoid tissue, remains undifferentiate in extrafollicular foci as short-lived plasmablasts characterized. TFH cells drive GC on their lack of FOXP3 expression (Li and Pauza, 2015), even B cell differentiation into long-lived plasma cells and memory though functional studies are lacking

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Conclusion