Metabolic signaling dictates context-dependent Treg cell functional heterogeneity - ABSTRACT
Regulatory T (Treg) cells play central roles in the establishment of immune tolerance but are barriers to anti-tumor
immunity and immunotherapy. In response to immune- and microenvironment-derived signals, Treg cells undergo
activation and differentiation from quiescent central Treg (cTreg) cells into an activated Treg cell population called
effector Treg (eTreg) cells with heightened suppressive function. How Treg cells are fated for eTreg cell differentiation
and functional programming in different immune contexts and tissue microenvironments remains poorly defined.
Further, although the concept of Treg cell heterogeneity (beyond the cTreg versus eTreg cell paradigm) is evolving,
the molecular processes shaping such heterogeneity and the functional effects remain poorly understood.
Metabolic reprogramming is emerging as a regulator of Treg cell identity, differentiation, and function. Our lab has
established mTORC1-orchestrated nutrient signaling and metabolic rewiring, including mitochondrial metabolic
fitness, as important drivers of eTreg cell differentiation or maintenance. Although these effects are attributed to
reduced mTORC1 signaling, hyperactivation of mTORC1 in Treg cells drives impaired eTreg cell lineage stability
and survival, associated with a loss of immune tolerance while simultaneously improving anti-tumor responses.
Thus, metabolic processes act as a rheostat to control eTreg cell functional fitness in diverse contexts, and
uncovering upstream signals that regulate intracellular metabolic reprogramming in Treg cells may reveal novel
ways to boost their function in autoimmune or inflammatory diseases or limit their activity in the tumor
microenvironment (TME). In our preliminary studies, using genetic models of Treg cell-specific gene deletion in
vivo, we uncovered a role for metabolic signaling complexes in shaping the generation of distinct eTreg cell
functional states that establish tumor immunosuppression versus tissue tolerance. Specifically, we applied Treg-
specific genetic targeting approaches to disrupt multiple components of autophagy- and endosome-associated
pathways. Our preliminary data show that Treg cell-specific deletion of such genes led to markedly disrupted
immune homeostasis, causing mice to develop a fatal Scurfy-like inflammatory disorder in conjunction with
improved anti-tumor responses. Such effects were associated with altered eTreg cell accumulation and metabolic
fitness and mechanistically were partly attributed to autophagy but not to endosome activity. My central
hypothesis is that metabolism-associated signaling and processes downstream of autophagy initiation and
endosome maturation facilitate context-dependent Treg cell functional adaptation and heterogeneity. Further,
targeting such molecules may represent a novel means to tune Treg cell function in autoimmune or inflammatory
diseases and cancer. Through the completion of three complementary but independent Aims, I will establish the
cellular and molecular mechanisms of eTreg cell accumulation and function that are mediated by autophagy-
related molecules i) under steady state and ii) within the tumor microenvironment, as well as expand my studies
to iii) determine the role of endosome-associated molecules in the maintenance of Treg cell functional fitness.
