IL-7R\u03b1 glutamylation and activation of transcription factor Sall3 promote group 3 ILC development

Benyu Liu,Jiayi Wu,Ying Du,Zusen Fan,Yong Tian,Liuliu Yang,Guanling Huang,Buqing Ye,Shu Meng,Xiaoxiao Zhu,Pingping Zhu

doi:10.1038/s41467-017-00235-x

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.

Highlights

Group 3 innate lymphoid cells (ILC3) promote lymphoid organogenesis and potentiate immune responses against bacterial infection
We previously demonstrated that deficiency in CCP5 or CCP6 leads to susceptibility to virus infection[29]
We analyzed ILC3s (Lin−CD45+RORγt+) in the small intestine lamina propria in all six deficient mouse strains and found that the number of ILC3 cells was significantly increased in Ccp2−/− mice, but not in other cytosolic carboxypeptidases (CCPs) KO mouse strains (Fig. 1a and Supplementary Fig. 1b, c)

Summary

Introduction

Group 3 innate lymphoid cells (ILC3) promote lymphoid organogenesis and potentiate immune responses against bacterial infection. IL-7Rα polyglutamylation triggers STAT5 activation to initiate transcription factor Sall[3] expression in common helper-like innate lymphoid progenitors, which drives ILC3 cell differentiation. Group 3 innate lymphoid cells (ILC3), including lymphoid tissue inducer (LTi) cells, natural cytotoxicity receptor positive (NCR+) and NCR− ILC3s, promote lymphoid organogenesis and potentiate immune responses against bacterial infection, respectively, via producing cytokines IL-17 and IL-2210–12. ILC3s, together with other ILCs, are derived from the earliest α-lymphoid progenitor cells (αLPs, CXCR6+ integrin α4β7-expressing CLPs)[2], which differentiate into common helper-like innate lymphoid progenitor (CHILP) cells[14]. IL-7Rα glutamylation enhances STAT5 activation and promotes Sall[3] transcription in CHILPs that drives the development of ILC3s. IL-7Rα glutamylation has a critical function in ILC3 development

Methods

Results

Conclusion