Zbtb20 Restrains CD8 T Cell Immunometabolism and Restricts Memory Differentiation and Antitumor Immunity

Yanbo Sun; Nicholas K. Preiss; Kristine B. Valenteros; Yasmin Kamal; Young-Kwang Usherwood; H. Robert Frost; Edward J. Usherwood

doi:10.4049/jimmunol.2000459

Key Points

Zbtb20 is an important regulator of effector and memory CD8 T cell immunometabolism.
Differentiation to a memory precursor phenotype is favored by Zbtb20 deficiency.
CD8 T cells deficient in Zbtb20 confer enhanced protection against tumors.

Abstract

CD8 T cell differentiation is orchestrated by dynamic metabolic changes that direct activation, proliferation, cytotoxic function, and epigenetic changes. We report that the BTB-ZF family transcriptional repressor Zbtb20 negatively regulates CD8 T cell metabolism and memory differentiation in mice. Effector and memory CD8 T cells with conditional Zbtb20 deficiency displayed enhanced mitochondrial and glycolytic metabolism, and memory CD8 T cells had enhanced spare respiratory capacity. Furthermore, Zbtb20-deficient CD8 T cells displayed increased flexibility in the use of mitochondrial fuel sources. Phenotypic and transcriptional skewing toward the memory fate was observed during the CD8 T cell response to Listeria monocytogenes. Memory cells mounted larger secondary responses and conferred better protection following tumor challenge. These data suggest that inactivation of Zbtb20 may offer an approach to enhance metabolic activity and flexibility and improve memory CD8 T cell differentiation, useful attributes for T cells used in adoptive immunotherapy.

Footnotes

This work was supported by National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases Grant R01 AI122854 (to E.J.U.), NIH/U.S. National Library of Medicine Grant K01 LM012426 (to H.R.F.), and NIH/National Institute of General Medical Sciences Centers of Biomedical Research Excellence Grant P20 GM130454 (to H.R.F.), which supported the Center for Quantitative Biology Single Cell Genomics Core and the Genomics and Molecular Biology Shared Resource at Dartmouth. The Center for Quantitative Biology Single Cell Genomics Core and the Genomics and Molecular Biology Shared Resource at Dartmouth is also supported by NIH/National Cancer Institute Cancer Center Support Grant 5P30CA023108-37. Imaging studies were performed at the Dartmouth Institute for Biomolecular Targeting, supported by NIH Grant P20 GM113132.
The online version of this article contains supplemental material.