Specific expression of a BTB-ZF transcription factor defines innate-like regulatory T cells that are essential for intestinal homeostasis

Abstract

Abstract Regulatory T cells (Tregs) play a pivotal role in regulating immune responses and are a significant source of the anti-inflammatory cytokine IL-10 in the intestine. Defects in Tregs function lead to the development of systemic and intestinal inflammation. Using a single-cell BTB-ZF transcription factor expression analysis, we identified a distinct subset of Tregs. These cells have an activated phenotype (CD62Llo, CD44hi) and constitutively express the Il10. Moreover, these Tregs accumulate in the intestine and expand in number following DSS induced colitis. The targeted deletion of the defining transcription factor impaired these cells' ability to secrete IL-10, leading to significant disruptions in mucosal architecture and the development of intestinal inflammation following treatment with dextran sodium sulfate (DSS). Thus, the conditional knockout (cKO) mice developed much more severe symptoms leading to the death of 60% of them. In contrast, all wild type mice fully recovered. Notably, adoptive transfer of this Treg subset was sufficient to prevent the death of cKO mice. In comparison, the transfer of cKO Tregs was not able to rescue the mice. Collectively, our data show that we have identified a distinct subset of Tregs and determined a specific member of the BTB-ZF family that controls their function. This rare population of T cells has potent immunosuppressive abilities and, we propose, rather than acutely producing IL-10 in response to activation, these cells maintain intestinal homeostasis through continuous secretion of IL-10. Our findings imply that analogous to NKT cells, some thymic-derived Tregs have innate-like effector functions that are not dependent upon differentiation in the periphery.