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

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 IL-2 at the T-B border and within interfollicular (IF) regions, and that this localized IL-2 is required to maintain GALT Treg 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 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-derived IL-2 niche critical for GALT Treg stability and uncover an unexpected immunoregulatory role for Tfh cells in maintaining gastrointestinal tolerance beyond B cell help.