Interleukins 12 and 15 induce cytotoxicity and early natural killer cell differentiation in type 3 innate lymphoid cells

Type 3 innate lymphoid cells (ILC3s) fulfill protective functions at mucosal surfaces via cytokine production. While their plasticity to become ILC1s, the innate counterparts of type 1 helper T cells, has been described previously, we report that they can differentiate into cytotoxic lymphocytes with many characteristics of early differentiated natural killer (NK) cells. This transition is promoted by the proinflammatory cytokines IL-12 and IL-15, and correlates with expression of the master transcription factor of cytotoxicity eomesodermin (Eomes). As revealed by transcriptome analysis and flow cytometric profiling, differentiated ILC3s express CD94, NKG2A, NKG2C, CD56 and CD16 among other NK cell receptors, and possess all components of the cytotoxic machinery. These characteristics allow them to recognize and kill leukemic cells. Therefore, ILC3s can be harnessed for cytotoxic responses via differentiation under the influence of proinflammatory cytokines. Expression profiling (RNA-Seq) of NKp44+ innate lymphoid cells (ILC) derived from pediatric tonsils and spleens of NOD SCID-/-γc-/- mice reconstituted with human hematopoietic progenitor cells. Three experiental groups were compared: not cultured ILCs, ILCs cultured with IL-2 and IL-7, and ILCs cultured with IL-12 and IL-15.