IL-2 production by Tfh cells is critical for peripheral tolerance maintenance

Whether Tfh cells play additional immunoregulatory roles beyond B cell help remains unclear. We demonstrate that T follicular helper (Tfh) cells in mesenteric lymph nodes and Peyer’s patches produce substantial amounts of IL-2 under steady-state conditions.

Strikingly, conditional deletion of IL-2 from Tfh cells results in severe multi-organ inflammation, not due to disruptions in germinal center B cell responses, but rather due to impaired homeostasis of Foxp3⁺CD25⁺ Tregs. Phenotypic and transcriptional analyses collectively highlight that IL-2 production by Tfh cells is essential for maintaining Treg competitive fitness in the gastrointestinal tract. Specifically, it helps maintain a balance between homeostatic RORγ⁺ Tregs and pathogenic Th1-like T-bet⁺ Tregs.