One critical aspect impacting on T cell proliferation and function is the host environment. The activation and effector functions of adoptively-transferred T lymphocytes are associated with increased energetic and biosynthetic demands, generally secured by augmented nutrient entry and utilization. However, the potential of an engineered anti-tumor T cell (using a chimeric antigen receptor (CAR) or T cell receptor (TCR)) to respond to tumor antigens is often negatively modulated by the metabolic environment of the tumor. This environment is conditioned by nutrient composition, waste products, oxygen concentration, pH and physical forces, amongst others. The dysregulated growth of cancer cells can directly influence the extracellular environment and negatively impact on the ensuing immune response. These differences in metabolite environment may account for at least one of the mechanisms modulating the success of CAR-T cells directed against diffuse leukemias (i.e. CD19-CAR) as compared to solid tumors. Indeed, we have found that the differential use of glutamine and glucose regulates T cell differentiation and function. Remarkably, glutamine deprivation causes naive CD4+ T cells to differentiate into suppressor regulatory T cells, even under Th1 polarizing conditions while high Glut1 levels promote effector cytokine secretion. Indeed, we have identified alpha-ketoglutarate, a metabolite derived from glutamine, as a regulator in the balance between Th1 vs Treg differentiation and ongoing studies are evaluating the impact of myeloablative and non-myeloablative chemotherapy regimens in the metabolic microenvironment. Furthermore, we have found that glutaminolysis is the major pathway fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in TCR-stimulated naive as well as memory CD4 subsets and reveal the critical importance of this pathway in regulating HIV-1 infection. Specifically, we show that Increasing the allocation of glucose carbons to the TCA cycle and pentose phosphate pathway results in a significant increase in HIV-1 reverse transcription. Therefore, we identify the OXPHOS-aerobic glycolysis balance as a regulator of HIV-1 infection in CD4 T lymphocytes.
