Transcription factor IRF4 and ThPOK regulates ILC3 lineage homeostasis and function during intestinal infection

Abstract

The work described in this thesis adds several factors as essential regulators to the list of transcriptional network effectors that guide the development of ILC3s, including IRF4, GATA3, Tbx21, ThPOK, and RORγt. This study describes how these transcriptional networks interact in vivo to control the functionality and phenotypical polarization of mature ILC3 subpopulations, illustrating the complicated interactions between classical ILC-associated TFs and their varying post-developmental requirements. IRF4 sustained ILC3s maintenance, as mice lacking IRF4 displayed dysregulated phenotype and function, resulting in increased susceptibility to C. rodentium and Candida albicans infection. The integrated analysis revealed that IRF4 sustains ILC3 function and maintenance via directly binding to Il17a, Il22, and Gata3. Another highly conserved transcription factor ThPOK sustained the maintenance of ILC3s, as ThPOK deficient mice displayed reduced NKp46 positive ILC3s and rising DN ILC3s. Loss of ThPOK also impaired the IFN-γ production of NKp46⁺ ILC3s, leading to increased susceptibility to S. Typhimurium infection. On the contrary, ThPOK modulates ILC3-mediated immunity against C. rodentium infection by negatively controlling IL-17A production through the IL-23/IL-17 axis. Taken together, this thesis has enabled preliminary integrated analysis of the interplay among ThPOK, RORγt, IRF4, GATA3, and T-bet to modulate ILC3 functionality and induce the balance of transition programs within ILC3 subpopulations. These findings emphasize the significance of taking into account both antagonistic and cooperative transcription factors as this thesis intends to clarify how ILCs retain their identity and essential functions after development and hence preserve tissue homeostasis.