Zbtb20 identifies and controls a thymus-derived population of regulatory T cells that play a role in intestinal homeostasis.

The expression of BTB-ZF transcription factors such as ThPOK in CD4 T cells, Bcl6 in T follicular helper cells, and PLZF in natural killer T cells defines the fundamental nature and characteristics of these cells. Screening for lineage-defining BTB-ZF genes led to the discovery of a subset of T cells that expressed Zbtb20. About half of Zbtb20 T cells expressed FoxP3, the lineage-defining transcription factor for regulatory T cells (T). Zbtb20 T were phenotypically and genetically distinct from the larger conventional T population. Zbtb20 T constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20 T were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of in T cells resulted in a loss of intestinal epithelial barrier integrity. Consequently, knockout (KO) mice were acutely sensitive to colitis and often died because of the disease. Adoptive transfer of Zbtb20 T protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 T did not. Zbtb20 was detected in CD24 double-positive and CD62L CD4 single-positive thymocytes, suggesting that expression of the transcription factor and the phenotype of these cells were induced during thymic development. However, Zbtb20 expression was not induced in "conventional" T by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of T that are involved in intestinal homeostasis.