Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells

Leena Chaudhuri, Rupesh K. Srivastava, Ferdynand Kos, Protul A. Shrikant

Research output: Contribution to journalReview article

7 Citations (Scopus)

Abstract

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 (CD62LloKLRG1HiIFNγHi) 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.

Original languageEnglish (US)
Pages (from-to)869-874
Number of pages6
JournalCancer Immunology, Immunotherapy
Volume65
Issue number7
DOIs
StatePublished - Jul 1 2016

Fingerprint

CD8 Antigens
T-Lymphocytes
Cell Differentiation
Cell- and Tissue-Based Therapy
Antigens
Uncoupling Protein 2
Mitochondrial Proteins
Neoplasm Antigens
Glycolysis
Small Interfering RNA
Reactive Oxygen Species
Neoplasms
Cell Survival
Fatty Acids

Keywords

  • CD8+ T cell fate
  • CITIM 2015
  • Metabolic reprogramming
  • Uncoupling protein 2

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Medicine(all)
  • Oncology
  • Cancer Research

Cite this

Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells. / Chaudhuri, Leena; Srivastava, Rupesh K.; Kos, Ferdynand; Shrikant, Protul A.

In: Cancer Immunology, Immunotherapy, Vol. 65, No. 7, 01.07.2016, p. 869-874.

Research output: Contribution to journalReview article

Chaudhuri, Leena ; Srivastava, Rupesh K. ; Kos, Ferdynand ; Shrikant, Protul A. / Uncoupling protein 2 regulates metabolic reprogramming and fate of antigen-stimulated CD8+ T cells. In: Cancer Immunology, Immunotherapy. 2016 ; Vol. 65, No. 7. pp. 869-874.
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