Tissue microenvironment dictates the fate and tumor-suppressive function of type 3 ILCs

Innate lymphoid cells (ILCs) have been classified into “functional subsets” according to their transcription factor and cytokine profiles. Although cytokines, such as IL-12 and IL-23, have been shown to shape plasticity of ILCs, little is known about how the tissue microenvironment influences the plasticity, phenotype, and function of these cells. Here, we show clearly demarcated tissue specifications of Rorc-dependent ILCs across lymphoid and nonlymphoid organs. Although intestinal Rorc fate map–positive (Rorc(fm+)) ILCs show a clear ILC3 phenotype, lymphoid tissue–derived Rorc(fm+) ILCs acquire an natural killer (NK) cell/ILC1-like phenotype. By adoptively transferring Rorc(fm+) ILCs into recipient mice, we show that ILCs distribute among various organs and phenotypically adapt to the tissue environment they invade. When investigating their functional properties, we found that only lymphoid-tissue resident Rorc(fm+) ILCs can suppress tumor growth, whereas intestinal Rorc(fm−) ILC1s or NK cells fail to inhibit tumor progression. We thus propose that the tissue microenvironment, combined with ontogeny, provides the specific function, whereas the phenotype is insufficient to predict the functional properties of ILCs.