Foxp3+ regulatory T (TR) cells are pivotal to the maintenance of peripheral immunological tolerance. This complex population includes the ?natural? TR (nTR) lineage that develops in the thymus and the comparatively unstable ?induced? TR (iTR) cells that arise from conventional T cells in the periphery. Loss of function Foxp3 mutations in humans and in mice give rise to TR cells lacking in regulatory activities, resulting in fatal autoimmunity. In Foxp3-sufficient hosts, instability of Foxp3 expression in iTR cells, especially under inflammatory conditions, gives rise to Foxp3-deficient ex-iTR cells that are pathogenic. Foxp3 deficient TR cells continue to express core elements of the canonical TR transcriptional signature. However, they also acquire a phenotype and transcriptional profile similar to terminally differentiated effector T (TEff)-like cells. They switch their energy metabolism to aerobic glycolysis, exhibit mTORC1 and mTORC2 activation and produce Th1, Th2 and Th17 cytokines that contribute to systemic inflammation. The molecular mechanisms mediating the acquisition by Foxp3-deficient TR cells of a TEff phenotype and the abrogation of their suppressive function remain obscure. To elucidate these mechanisms, we have created a novel mutant Foxp3 allele (Foxp?EGFPiCre) that simultaneously abrogates expression of Foxp3 while driving the expression of a humanized Cre recombinase (iCre) fused with an enhanced green fluorescent protein (EGFP). We demonstrate that Foxp?EGFPiCre TR (?TR) cell-specific deletion of Rictor, which encodes an essential component of the mammalian target of Rapamycin complex 2 (mTORC2), substantially ameliorates the disease associated with Foxp3 deficiency. Rictor deletion in ?TR cells restores nuclear Foxo1 localization, suppresses Th1 programing, inhibits aerobic glycolysis, and partially rescues regulatory activity. Accordingly, we hypothesize that TR cell failure due to genetic or acquired Foxp3 deficiency is driven by the dysregulation of a limited but critical set of molecular pathways, including the mTORC2/AKT/Foxo1 axis and metabolic regulators of aerobic glycolysis, that together oversee the transformation of the ?TR and ex-TR cells into TEff -like cells. In this proposal, we will examine the mechanisms by which dysregulation of these pathways impair ?TR cell function. We will then use mTORC2/AKT/Foxo1 axis inhibition and metabolic reprogramming to improve the stability and function of iTR cells in TR-cell based treatment models of autoimmune disease. The proposed experiments will elucidate the pathogenesis of autoimmune or dysregulatory diseases stemming from genetic or acquired loss of Foxp3 expression. Critically, they will enable the creation of new therapies designed to rescue the regulatory activity of dysfunctional TR cells. Such therapeutic approaches are eminently applicable to boosting TR cell function in common disease states that include autoimmunity and graft versus host disease.
Regulatory T (TR) cells play an essential role in regulating immune responses to self- tissues and to benign environmental agents such as foods. Their deficiency, caused by a number of heritable genetic defects, leads to severe autoimmune and inflammatory complications that can be life threatening or fatal. Many individuals suffering from TR cell deficiency have mutations in the transcription factor FOXP3, which endows TR cells with their immune regulatory functions. TR cells may also lose FOXP3 expression in the context of chronic inflammation, as seen in a number of autoimmune and inflammatory diseases, contributing to the perpetuation of these debilitating conditions. We are proposing to reprogram immune regulatory functions in TR cells lacking FOXP3 by resetting deleterious pathways let loose by its deficiency. Our studies hold the promise of novel therapies that are broadly applicable to disorders of failed immune regulation, including not only genetic deficiency of FOXP3 but also inflammatory and autoimmune diseases common in the general population.
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