Ikaros Regulates IL-22-producing Immune Cell Responses by Targeting Distinct Molecular Events

It is widely appreciated that Ikaros is critical for lymphoid cell development from the early common hematopoietic progenitor cell. Ikaros has been found to be involved in some subsets of T helper cells; however, its role in regulating the TGF-beta- and/or Stat3-induced Treg, Th17, and Th22 cell subsets remains unclear. In addition, a role for Ikaros in the T helper-like innate lymphoid cells has not yet been established. This thesis describes how Ikaros plays a critical role in regulating IL-22-producing CD4+ T helper cells as well as their innate lymphoid cell counterparts, ILC3s. Interestingly, our data show that mice lacking functional full-length zinc finger transcription factor Ikaros had increases in both IL-22- but not IL-17-producing CD4 + T cells and ILC3s in the gut. Adoptive transfer of CD4+ T cells lacking wildtype Ikaros conferred enhanced mucosal immunity against Citrobacter rodentium infection. Aberrant upregulation of IL-21 in CD4+ T cells expressing mutant Ikaros was at least in part responsible for the enhanced IL-22 and IL-17 expression in a Stat3-dependent manner. Genetic analysis using compound mutations further demonstrated that the aryl hydrocarbon receptor (Ahr), but not RORgammat, was required for aberrant IL-22 expression by Ikaros mutant CD4+ T cells. The increased population of ILC3s in mice lacking full-length wildtype Ikaros required both Ahr and RORgammat, and the Ikaros mutant ILC3s expressed high levels of CCR6, which likely responsible for increased numbers of cryptopatches. Thus, this body of work promotes two novel concepts: one, that Ikaros is important for regulating the adaptive Th22 cells and two, that Ikaros plays an important role in the innate IL-22-producing ILC3 subset.