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Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.

Adoptive cell transfer (ACT) therapy using tumor infiltrating lymphocytes (TILs) or T cells modified to express chimeric antigen receptors is a promising anti-cancer approach. Evidence suggests that Th17 or Tc17 cells display superior anti-tumor activity over unpolarized T cells commonly used in ACT clinical trials. As an approach to improve the potency and persistence of ACT, synthetic RORɣ agonists were designed to bolster the generation of type 17 cells. In vitro stimulation in the presence of RORɣ agonists modulates expression of costimulatory and coinhibitory molecules and increases IL-17A, IL-22 and GM-CSF production while maintaining IFNɣ production. Additional investigation revealed that treating tumor-specific Th0, Th17, Tc0 or Tc17 T cells with a RORɣt agonist in vitro significantly enhanced their ability to regress large and established EG.7 lymphoma and B16F10 melanoma tumors in vivo. Animals receiving RORɣ agonist-treated T cells had increased frequency of transferred cells, elevated IL-17A levels and decreased PD-1 expression in tumors and spleen compared to control animals. Previous studies have also shown that systemic delivery of an RORɣ agonist can also enhance anti-tumor immune response in syngeneic pre-clinical tumor models. By enhancing cytokine/chemokine production, promoting survival as well as decreasing PD-1 expression, RORɣ agonist molecules provide an effective means to enhance the potency of adoptively transferred T cell products.