Project Summary: Proper immune function is pivotal to the human health. CD4+ T cell is a central component of adaptive immunity to coordinate both innate and adaptive immune responses. Immune suppressive regulatory T (Treg) cells are pivotal in immune homeostasis and self-tolerance, and their function is controlled through quite diverse mechanisms, allowing Treg cells to respond appropriately to diverse environmental cues to ensure proper immune response. It is important to investigate the functional protein networks underlying T and Treg cell function in immune homeostasis and diseases. We have identified many critical factors, pathways, and mechanisms for T and Treg cell function in the last funding period, during which we revealed an unexpected critical role for an innate senor AIM2 (Absent In Melanoma 2) in controlling Treg cell function in a recent study. We found that AIM2 is expressed at much higher levels in Treg cells than in innate cells, in both human and mouse. TGFβ promotes AIM2 expression coinciding with Treg cell generation. Unlike Asc-/- and ICE-/- (caspase-1-/-11-/--) mice that are resistant to EAE, Aim2-/- mice developed more severe EAE than WT mice. AIM2 deletion leads to reduced Treg cell function during inflammatory diseases such as EAE. AIM2 is required for Treg cell stability to mitigate EAE. AIM2-deficiency leads to the hyper-activation of Akt-mTOR signaling to attenuate Treg cell function with altered immune metabolism. These exciting findings prompt us to hypothesize that the expression and function of AIM2 in Treg cells are controlled through mechanisms both distinct from and shared with those found in the innate cells, to uphold tolerance and restrain autoimmunity. To test this hypothesis, we strive to reach the following research aims. AIM 1: Reveal the genetic and molecular mechanisms of TGFβ promoted Aim2 expression in Treg cells. AIM 2: Investigate if AIM2 controls Treg cell function by integrating DNA-sensing function and inflammasome components. AIM 3: Mechanistic study of the functional AIM2-interacting protein network underlying AIM2 controlled Treg cell function. This proposed study will highlight a previously unappreciated critical role for AIM2 in Treg cells. It will revise the current paradigm for the function of AIM2 by incorporating its Treg cell specific function. It will provide new insights into how Treg cell generation and function can be regulated. It will shed new lights on the molecular networks underlying Treg cell function and to reveal potential novel molecular targets and therapies for autoimmune diseases.