AbstractIL‐22 is a Th17 cytokine that plays a key role in immune responses against extracellular bacteria. In mucosal lymphoid tissues, IL‐22 production is mainly due to an IL‐23‐responsive NK‐like cell subset that shares some markers with lymphoid tissue inducer (LTi) cells. Here, we identified a new spleen cell population responsible for IL‐22 production upon either in vitro stimulation by anti‐CD3 antibodies or in vivo stimulation by lipopolysaccharide (LPS) via IL‐2‐ and an IL‐23‐dependent mechanisms, respectively. These cells represent 1% of spleen cells from recombination activating gene (Rag2)‐deficient mice, and correspond to a discrete innate lymphoid cell population expressing CD25, CCR6 and IL‐7R. This population comprises 60–70% CD4+ cells, which produce IL‐22, and are still present in common γ chain‐deficient mice; the CD4− subset coexpresses IL‐22 and IL‐17, and is common γ chain‐dependent. The importance of IL‐22 production for the LPS‐triggered response is highlighted by the fact that IL‐22‐deficient mice are more resistant to LPS‐induced mortality.