IL-2-producing TFH cells sustain Treg cell homeostasis and immune tolerance in the gut.

Abstract

Follicular helper T (T_FH) cells are well known for their role in supporting B cell responses. Here, we identify a critical B cell-independent function for T_FH cells in sustaining regulatory T (T_reg) cells within gut-associated lymphoid tissues (GALT). We demonstrate that T_FH cells produce interleukin-2 (IL-2) at the T cell-B cell border and within interfollicular regions and that this localized IL-2 is required to maintain GALT T_reg cell homeostasis and restrain the expansion of pathogenic effector T cells. Mice selectively lacking IL-2-producing T_FH cells develop colitis and fatal multiorgan inflammation, driven by impaired GALT T_reg cell responses and uncontrolled effector T cell activation. Broad-spectrum antibiotic treatment alleviates both intestinal and extraintestinal pathology, indicating that loss of tolerance to commensal-derived antigens is a key driver of disease. Together, these findings define a spatially restricted T_FH cell-derived IL-2 niche critical for GALT T_reg cell stability and uncover an unexpected immunoregulatory role for T_FH cells in maintaining gastrointestinal tolerance beyond B cell help.