Acute mucosal infections remain a foremost global health problem. ROR?t and IL23/STAT3 signaling in ROR?t+ group-3 innate lymphoid cells (ILC3s) are critical for IL-22 production required for protection against Citrobacter rodentium colitis. We recently showed that lymphotoxin (LT) from ILC3s could also control IL-22 production. IL-7R signaling is required for maintaining ILC3s. The transcription factor Id2 is required for ILC progenitor development, since Id2-/- mice lack all ILC lineages;however, Id2 is still highly expressed after ILC3 development, and it remains unclear whether or not Id2 regulates the function of differentiated ROR?t+ ILC3s and, if so, how this is executed. To address the role of Id2 in the homeostasis and/or function of ILC3s, we generated mice deficient in Id2 only in their ROR?t+ ILC3s (ROR?t-Id2-/- mice) and observed that they have reduced ILC3s with diminished IL-7R, IL-23R, LT and IL-22 expression and became highly susceptible to C. rodentium infection. Surprisingly, cohousing ROR?t-Id2-/- mice with WT mice reduced mortality and morbidity of ROR?t-Id2-/- mice. We hypothesize that Id2 expression in differentiated ROR?t+ ILC3s is required for the homeostasis and function of ILC3s, which can control commensal flora against pathogen colonization in the gut.
In Aim 1, we will determine how Id2 regulates the development of various ILC3 subsets. We will test whether or not Id2 is required to control the IL-7R pathway and how this is regulated. We will also study whether or not Id2 controls the survival or proliferative capacity of ILC3s through IL-7R signaling. Finally, we will determine how interaction of Id2 and E protein controls the IL-7R/STAT5 pathway.
In Aim 2, we will define how Id2 controls host defense against C. rodentium infection. We will test whether or not Id2 expression in ILC3s promotes IL-22 production, which is required for protection against C. rodentium infection. We will test whether Id2 intrinsically regulates IL-22 production through the IL-23R pathway to protect the host against an infection. We will also determine how Id2 controls LT expression on ILC3s for extrinsic regulation of IL-22 production against C. rodentium infection.
In Aim 3, we will determine whether Id2 controls C. rodentium infection through regulating and maintaining a gut flora capable of competing with C. rodentium. If so, we will test how an Id2- dependent response regulates the protective gut flora against C. rodentium. We will further determine whether the selection is mediated by ILC3-derived IL-22. Finally, we will determine how an Id2- dependent gut flora controls C. rodentium infection. Studying Id2 in ROR?t+ ILC3s will provide new insights into ILC3 development and function, which contribute to the homeostasis of gut flora that protects against a mucosal infection in the gut.
Acute mucosal infections are currently the foremost global health problem. This study will advance our current understanding of a critical step in lymphoid development and the critical mechanism by which newly defined innate lymphoid cells control gut infections.
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