Abstract
Group 3 innate lymphoid cells (ILC3) promote lymphoid organogenesis and potentiate immune responses against bacterial infection. However, how ILC3 cells are developed and maintained is still unclear. Here, we show that carboxypeptidase CCP2 is highly expressed in common helper-like innate lymphoid progenitors, the progenitor of innate lymphoid cells, and CCP2 deficiency increases ILC3 numbers. Interleukin-7 receptor subunit alpha (IL-7Rα) is identified as a substrate of CCP2 for deglutamylation, and IL-7Rα polyglutamylation is catalyzed by polyglutamylases TTLL4 and TTLL13 in common helper-like innate lymphoid progenitors. IL-7Rα polyglutamylation triggers STAT5 activation to initiate transcription factor Sall3 expression in common helper-like innate lymphoid progenitors, which drives ILC3 cell differentiation. Moreover, Ttll4 -/- or Ttll13 -/- mice have reduced IL-7Rα polyglutamylation and Sall3 expression in common helper-like innate lymphoid progenitors. Importantly, mice with IL-7Rα E446A mutation have reduced Sall3 expression and ILC3 population. Thus, polyglutamylation and deglutamylation of IL-7Rα tightly controls the development and effector functions of ILC3s.Innate lymphoid cells (ILC) are important regulators of mucosal immunity, but how their development and homeostasis are modulated is still unclear. Here the authors show that the differentiation of group 3 ILCs is controlled by the glutamylation of IL-7Rα and the induction of transcription factor Sall3.