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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 regs ). Zbtb20 + T regs were phenotypically and genetically distinct from the larger conventional T reg population. Zbtb20 + T regs constitutively expressed mRNA for interleukin-10 and produced high levels of the cytokine upon primary activation. Zbtb20 + T regs were enriched in the intestine and specifically expanded when inflammation was induced by the use of dextran sodium sulfate. Conditional deletion of Zbtb20 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 regs protected the Zbtb20 conditional KO mice from severe colitis and death, whereas non-Zbtb20 T regs did not. Zbtb20 was detected in CD24 hi double-positive and CD62L lo 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 regs by activation in vitro or in vivo. Thus, Zbtb20 expression identified and controlled the function of a distinct subset of T regs that are involved in intestinal homeostasis.