Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells.
Adoptive cell therapy (ACT) employing ex vivo-generated tumor antigen-specific CD8+ T cells shows tumor efficacy when the transferred cells possess both effector and memory functions. New strategies based on understanding of mechanisms that balance CD8+ T cell differentiation toward effector and memory responses are highly desirable. Emerging information confirms a central role for antigen-induced metabolic reprogramming in CD8+ T cell differentiation and clonal expansion. The mitochondrial protein uncoupling protein 2 (UCP2) is induced by antigen stimulation of CD8+ T cells; however, its role in metabolic reprogramming underlying differentiation and clonal expansion has not been reported. Employing genetic (siRNA) and pharmacologic (Genipin) approaches, we note that antigen-induced UCP2 expression reduces glycolysis, fatty acid synthesis and production of reactive oxygen species to balance differentiation with survival of effector CD8+ T cells. Inhibition of UCP2 promotes CD8+ T cell terminal differentiation into short-lived effector cells (CD62L(lo)KLRG1(Hi)IFNγ(Hi)) that undergo clonal contraction. These findings are the first to reveal a role for antigen-induced UCP2 expression in balancing CD8+ T cell differentiation and survival. Targeting UCP2 to regulate metabolic reprogramming of CD8+ T cells is an attractive new approach to augment efficacy of tumor therapy by ACT.
Departments of Immunology, Molecular Pharmacology/Experimental Therapeutics and Research, Mayo Clinic Arizona, JRB 3-356, E. Shea Blvd, Scottsdale, AZ, 85259, USA.
Leena
L
Chaudhuri
Departments of Immunology, Molecular Pharmacology/Experimental Therapeutics and Research, Mayo Clinic Arizona, JRB 3-356, E. Shea Blvd, Scottsdale, AZ, 85259, USA.|Department of Zoology, School of Biological Sciences, Dr. Hari Singh Gour University, Sagar, MP, 470003, India.
Rupesh K
RK
Srivastava
Departments of Immunology, Molecular Pharmacology/Experimental Therapeutics and Research, Mayo Clinic Arizona, JRB 3-356, E. Shea Blvd, Scottsdale, AZ, 85259, USA.|Department of Experimental Therapeutics, Beckman Research Institute of the City of Hope, Duarte, CA, 91010, USA.
Ferdynand
F
Kos
Departments of Immunology, Molecular Pharmacology/Experimental Therapeutics and Research, Mayo Clinic Arizona, JRB 3-356, E. Shea Blvd, Scottsdale, AZ, 85259, USA. Shrikant.Protul@mayo.edu.
Protul A
PA
Shrikant
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D000071246:Uncoupling Protein 2 / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D000071246:Uncoupling Protein 2
CD8+ T cell fate; CITIM 2015; Metabolic reprogramming; Uncoupling protein 2