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

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.

T follicular regulatory cells and IL-10 promote food antigen–specific IgE

“…Whether there are very rare Tfr cells in humans that are clear counterparts to mouse Tfr cells or whether human Tfr cells consist of a variety of related follicular T cell populations that are distinct from mouse Tfr cells remains to be determined. Circulating Tfr cells have been examined extensively in humans (35,43,(46)(47)(48), however, the relationship of these cells to tissue-resident Tfr cells is not known. Much work remains to be done on human Tfr cells.…”

“…Furthermore, there is controversy about how to define human Tfr cells within lymphoid tissue. Although CD4 + CXCR5 + PD-1 ++ BCL6 + FOXP3 + Tfr cells are readily detected in mouse lymphoid tissues after immunization, analogous cell populations have been hard to find in human lymphoid tissues that contain GCs (43)(44)(45). Whether tissue-resident human Tfr cells uniformly express FOXP3, PD-1, or CD25 remains to be clarified (43)(44)(45).…”

Functions of Tfh Cells in Common Variable Immunodeficiency

“…Circulating FoxP3 + Tfr have been described (40). Cañete et al identified a population of IL-10 producing human TFH expressing CD25 but lacking FoxP3 in tonsils and capable of dampening IgE responses, thereby suggesting a possible role for these cells in atopic diseases (41). Altogether, despite several studies focused on TFH biology over the past decade, the functions of each human subset are not fully discovered yet.…”

“…IL-12 (54,55), TGFβ (56), Activin A (57), and OX40L (58, 59) The main characteristics of the circulating CD4 + CD45Ra − CXCR5 + follicular helper T cell subsets are described. *Both FoxP3+ and FoxP3 TFR have been reported (40,41).…”

T Follicular Helper Cell Subsets and the Associated Cytokine IL-21 in the Pathogenesis and Therapy of Asthma

“…It is thus of interest to see how T FR cells respond in asthma patients in future studies. Moreover, specialized human IL-10-producing CD25 + Foxp3 − T FR cells effectively control IgE production (126). In the most recent study, Clement et al revealed that T FR cells can limit T FH 13 cell-promoted IgE in mouse, and depletion of T FR cells enhances antigen-specific IgE antibody and exacerbates lung inflammation (62).…”