RESUMO
Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8+ T cells. Treatment of naïve CD8+ T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli, SPD bound to the α and ß subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell-specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation.
Assuntos
Linfócitos T CD8-Positivos , Mitocôndrias , Subunidade alfa da Proteína Mitocondrial Trifuncional , Subunidade beta da Proteína Mitocondrial Trifuncional , Neoplasias , Espermidina , Animais , Camundongos , Linfócitos T CD8-Positivos/imunologia , Ativação Linfocitária , Mitocôndrias/metabolismo , Subunidade alfa da Proteína Mitocondrial Trifuncional/metabolismo , Subunidade beta da Proteína Mitocondrial Trifuncional/metabolismo , Espermidina/farmacologia , Espermidina/metabolismo , Neoplasias/imunologiaRESUMO
Immunity developed to defend our bodies from foreign particles, including bacteria and viruses. Although effector cells responsible for acquired immunity, mainly T cells, and B cells, are able to distinguish self from non-self, they sometimes attack the body's tissues because of imperfect central tolerance. Several immune check points developed to limit overactivation of these cells. One of the most important immune checkpoints is programmed cell death-1 (PD-1), which is expressed mainly on activated lymphocytes. As its ligands (PD-Ls) are expressed widely in the body and affect the responses against self and foreign antigens, controlling PD-1/PD-L interactions enables the management of several immune-related diseases such as autoimmune disease, virus infection, and cancers. Currently, the strategy of PD-1/ PD-L1 blockade has already been applied to clinical cancer therapy, providing evidences that PD-1 signal is one of the main factors of cancer immune escape in humans. The dramatic efficacy of PD-1 blockade in cancer immunotherapy, promises the control of other immune diseases by PD-1 signal modulation. In this review, we summarize the history of PD-1, subsequent basic studies, and their application to the clinic.
