Innate gamma delta T cells expressing V gamma 6 produce IL-17A at an early stage following infection with Mycobacterium bovi s Bacillus Calmette-Guerin (BCG). In this study, we used IL-21 receptor knockout (IL-21R KO) mice and IL-21-producing recombinant BCG mice (rBCG-Ag85B-IL-21) to examine the role of IL-21 in the regulation of IL-17A-producing innate gamma delta T-cell response following BCG infection. IL-17A-producing V gamma 6 + gamma delta T cells increased in the peritoneal cavity of IL-21R KO mice more than in wild type mice after BCG infection. In contrast, the number of IL-17A-producing V gamma 6 + gamma delta T cells was significantly lower after inoculation with rBCG-Ag85B-IL-21 compared with control rBCG-Ag85B. Notably, exogenous IL-21 selectively induced apoptosis of IL-17A-producing V gamma 6 + gamma delta T cells via Bim. Thus, these results suggest that IL-21 acts as a potent inhibitor of a IL-17A-producing gamma delta T-cell subset during BCG infection.