Loss of UCP2 in CD4+ T cell promotes Th1/2 Pathogenic Phenotype

Abstract

Abstract Uncoupling protein 2 (UCP2) is an anion carrier protein located in the mitochondrial inner membrane. Mitochondria are the major sites for energy metabolism which is tightly linked with immune cell fate. In the present study, we have investigated UCP2’s function in T cells against murine melanoma model and the experimental autoimmune encephalomyelitis (EAE) model. Loss of UCP2 in CD4+ T cells showed a significant rise in the Th2/Th1 ratio. These cells exhibited an improved Th2 phenotype with increased production of nitric oxide (NO), and Inducible nitric oxide synthase (iNOS). Therefore, CD4+ T cells were treated with NOC-18, a source of NO, or L-NMMA, inhibitor for NOS to demonstrate NO-mediated Th2 polarization. Furthermore, Treatment of Ucp2 siRNA or, Genipin (inhibitor for UCP2) mimicked the effect of UCP2-/- CD4+ T cell with more cytotoxic markers and Th2/Th1 double positive cells. Transcriptomic and metabolomic analysis revealed the lower response of calcium influx by TCR activation and increased NLRF3 activation by uric acid in UCP2 deficient CD4+ T cells. Adoptive transfer of Genipin-treated Tyrp CD4+ cells exhibited superior tumor control as compared to Th1 and Th2, according to the findings. However, in UCP2-/- mice, the severity of EAE worsened, and heterogenic Th2 cells were infiltrated into the spinal cord. Our findings imply that the loss of UCP2 in CD4 increases Th2 polarization with a cytotoxic phenotype and may be relevant to various illnesses.