The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality.

Published

Journal Article

Tissue-resident memory CD8+ T (Trm) cells share core residency gene programs with tumor-infiltrating lymphocytes (TILs). However, the transcriptional, metabolic, and epigenetic regulation of Trm cell and TIL development and function is largely undefined. Here, we found that the transcription factor Bhlhe40 was specifically required for Trm cell and TIL development and polyfunctionality. Local PD-1 signaling inhibited TIL Bhlhe40 expression, and Bhlhe40 was critical for TIL reinvigoration following anti-PD-L1 blockade. Mechanistically, Bhlhe40 sustained Trm cell and TIL mitochondrial fitness and a functional epigenetic state. Building on these findings, we identified an epigenetic and metabolic regimen that promoted Trm cell and TIL gene signatures associated with tissue residency and polyfunctionality. This regimen empowered the anti-tumor activity of CD8+ T cells and possessed therapeutic potential even at an advanced tumor stage in mouse models. Our results provide mechanistic insights into the local regulation of Trm cell and TIL function.

Full Text

Duke Authors

Cited Authors

  • Li, C; Zhu, B; Son, YM; Wang, Z; Jiang, L; Xiang, M; Ye, Z; Beckermann, KE; Wu, Y; Jenkins, JW; Siska, PJ; Vincent, BG; Prakash, YS; Peikert, T; Edelson, BT; Taneja, R; Kaplan, MH; Rathmell, JC; Dong, H; Hitosugi, T; Sun, J

Published Date

  • September 17, 2019

Published In

Volume / Issue

  • 51 / 3

Start / End Page

  • 491 - 507.e7

PubMed ID

  • 31533057

Pubmed Central ID

  • 31533057

Electronic International Standard Serial Number (EISSN)

  • 1097-4180

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2019.08.013

Language

  • eng

Conference Location

  • United States