Treg cells have a crucial role in autoimmunity, as they can suppress the development/progression of autoreactive immune responses. We recently reported that reduced caloric intake protected mice from autoimmunity by promoting the activity of CD4+ regulatory T (Treg) cells (Liu et al. J. Immunol. 2012;188:2070). We had previously shown that nutritional status affected Treg cell activity via leptin (De Rosa et al. Immunity 2007;26:241). Leptin is an adipocytokine that directly modulates the activity of the mammalian target of rapamycin (mTOR) complex pathway, which has a central role in the control of metabolism and cell growth in Treg cells. We found that leptin was capable to directly control mTOR activity, which was reduced in mice with a restricted caloric intake that, interestingly, were protected from autoimmune disease (Procaccini et al. Immunity 2010;33:929). Based on those findings, we hypothesize that the function(s) of Treg cells can be influenced by leptin-mTOR, and this link could be manipulated to downregulate autoimmune responses. To test this hypothesis, we will use multiple integrated approaches: 1) To define the relevance of leptin-mTOR in the metabolic control of Treg cell responses in normal conditions and in autoimmunity; 2) To investigate the possibility of intervention on this pathways for the modulation of Treg cell activity in autoimmune diseases. All together, these studies will contribute to a better understanding, and possible manipulation, of immune pathways that are intimately involved in the development/progression of autoimmunity.
Autoimmune diseases develop and progress because of impaired mechanisms of immune tolerance, including a reduced function and/or number of CD4+ regulatory T cells. This proposal will study how leptin-mTOR influence the metabolic activity of CD4+ regulatory T cells in autoimmunity, to create grounds for the design of new approaches of therapeutic intervention in autoimmune diseases.
