IL-2-Producing Tfh Cells Sustain Treg Cell Homeostasis and Immune Tolerance in the Gut

Abstract

Follicular helper T (TFH) cells are well known for their role in supporting B cell responses. Here, we identify a critical B cell-independent function for TFH cells in sustaining regulatory T (Treg) cells within gut-associated lymphoid tissues (GALT). We demonstrate that TFH 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 Treg cell homeostasis and restrain the expansion of pathogenic effector T cells. Mice selectively lacking IL-2-producing TFH cells develop colitis and fatal multiorgan inflammation, driven by impaired GALT Treg 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 TFH cell-derived IL-2 niche critical for GALT Treg cell stability and uncover an unexpected immunoregulatory role for TFH cells in maintaining gastrointestinal tolerance beyond B cell help. Ballesteros-Tato and colleagues identify a spatially restricted follicular helper T cell-dependent interleukin-2 niche critical for regulatory T cell stability in gut-associated lymphoid tissues.