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

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.

ZBTB Transcription Factors: Key Regulators of the Development, Differentiation and Effector Function of T Cells

“…ZBTB20 is widely expressed in hematopoietic tissues, and promotes the long-term antibody responses by increasing the survival of BM plasma cells ( 22 ). ZBTB20 is transiently upregulated in activated CD8 + T cells, and in the steady state, its levels in CD8 + T-cell compartment are CD62L + CD44 + Tcm > CD62L - CD44 + Tem ≈ CD62L + CD44 - Tn > CD62L - CD44 - Te cells ( 178 ). Depletion of ZBTB20 in activated CD8 + Te cells, mediated by Gzmb -Cre, enhances the cellular glycolytic and mitochondrial metabolisms, and increases their mitochondrial fuel flexibility.…”

“…Depletion of ZBTB20 in activated CD8 + Te cells, mediated by Gzmb -Cre, enhances the cellular glycolytic and mitochondrial metabolisms, and increases their mitochondrial fuel flexibility. Importantly, ZBTB20-deficiency renders CD8 + T cells, both phenotypically and transcriptionally, toward memory cells with an enhanced ability to mount secondary responses ( 178 ). Thus, ZBTB20 represents an important regulator that restrains CD8 + T cell metabolism and Tm differentiation in mice ( Figure 2B ).…”

Transcription factor ZBTB20: What expression is telling us of its cellular function?

“…2B) (37). Zbtb20 expression was also shown in a subpopulation of memory T-lymphocytes (38). To our knowledge there is no evidence for Zbtb20 expression in the granulocyte lineage and other T-lymphocytes.…”

Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3

“…ZBTB20 is a transcriptional repressor with multiple functions, such as regulating inflammation, cell death, immunity and so on. 42 , 43 A study indicated that mice lacking ZBTB20 displayed abnormal growth rate, accompanied by high fatality and infertility, emphasizing the importance of ZBTB20 in organisms. 44 In another study, ZBTB20 knockout could effectively protect mice from endotoxin shock and sepsis and further analysis showed that ZBTB20 may function through promoting NF-κB activation.…”