@article{900d2e8bd55b4ca79374e111d6ab8704,
title = "TCF-1-Centered Transcriptional Network Drives an Effector versus Exhausted CD8 T Cell-Fate Decision",
abstract = "TCF-1 is a key transcription factor in progenitor exhausted CD8 T cells (Tex). Moreover, this Tex cell subset mediates responses to PD-1 checkpoint pathway blockade. However, the role of the transcription factor TCF-1 in early fate decisions and initial generation of Tex cells is unclear. Single-cell RNA sequencing (scRNA-seq) and lineage tracing identified a TCF-1+Ly108+PD-1+ CD8 T cell population that seeds development of mature Tex cells early during chronic infection. TCF-1 mediated the bifurcation between divergent fates, repressing development of terminal KLRG1Hi effectors while fostering KLRG1Lo Tex precursor cells, and PD-1 stabilized this TCF-1+ Tex precursor cell pool. TCF-1 mediated a T-bet-to-Eomes transcription factor transition in Tex precursors by promoting Eomes expression and drove c-Myb expression that controlled Bcl-2 and survival. These data define a role for TCF-1 in early-fate-bifurcation-driving Tex precursor cells and also identify PD-1 as a protector of this early TCF-1 subset. The initiation of the T cell exhaustion program remains poorly understood. In this study, Chen et al. define an effector (Teff) versus exhausted (Tex) CD8 T cell binary-fate decision during chronic infection and find that TCF-1 supports the Tex precursor development by antagonizing Teff-like cell differentiation through multiple transcription factors.",
keywords = "CD8 T cell exhaustion, PD-1, cancer, chronic infection, exhaustion, immunotherapy, transcriptional circuit",
author = "Zeyu Chen and Zhicheng Ji and Ngiow, {Shin Foong} and Sasikanth Manne and Zhangying Cai and Huang, {Alexander C.} and John Johnson and Staupe, {Ryan P.} and Bertram Bengsch and Caiyue Xu and Sixiang Yu and Makoto Kurachi and Herati, {Ramin S.} and Vella, {Laura A.} and Baxter, {Amy E.} and Wu, {Jennifer E.} and Omar Khan and Beltra, {Jean Christophe} and Giles, {Josephine R.} and Erietta Stelekati and McLane, {Laura M.} and Lau, {Chi Wai} and Xiaolu Yang and Berger, {Shelley L.} and Golnaz Vahedi and Hongkai Ji and Wherry, {E. John}",
note = "Funding Information: We thank the Wherry lab for helpful discussions. This work was supported by NIH grants ( AI105343 , AI117950 , AI082630 , AI112521 , AI115712 , AI108545 , and CA210944 ) and Stand Up 2 Cancer funding to E.J.W.; NIH grant HG009518 to H.J.; NIH grant CA234842 to Z. Chen; NIH grant AI114852 to R.S.H.; and NIH grant CA009140 to J.R.G. E.J.W. is supported by the Parker Institute for Cancer Immunotherapy, which supports the cancer immunology program at UPenn; S.F.N. is supported by an Australia NH&MRC C.J. Martin Fellowship ( 1111469 ) and the Mark Foundation Momentum Fellowship; and J.R.G. is supported by Cancer Research Institute-Mark Foundation Fellowship. Funding Information: We thank the Wherry lab for helpful discussions. This work was supported by NIH grants (AI105343, AI117950, AI082630, AI112521, AI115712, AI108545, and CA210944) and Stand Up 2 Cancer funding to E.J.W.; NIH grant HG009518 to H.J.; NIH grant CA234842 to Z. Chen; NIH grant AI114852 to R.S.H.; and NIH grant CA009140 to J.R.G. E.J.W. is supported by the Parker Institute for Cancer Immunotherapy, which supports the cancer immunology program at UPenn; S.F.N. is supported by an Australia NH&MRC C.J. Martin Fellowship (1111469) and the Mark Foundation Momentum Fellowship; and J.R.G. is supported by Cancer Research Institute-Mark Foundation Fellowship. Z. Chen and E.J.W. designed the complete study; Z. Chen performed the experiments with the help of S.F.N. Z. Cai, A.E.B. J.E.W. J.-C.B. J.R.G. E.S. and C.W.L.; Z. Chen and Z.J. performed scRNA-seq and computational analysis with R.S. S.M. R.S.H. and L.V.; Z. Chen and Z.J. designed the STIP analysis method with the support of H.J.; S.M. and Z. Chen performed STIP analysis with motif analysis with help from O.K.; Z. Chen, J.J. M.K. and L.M. performed RV generation with the support of G.V.; B.B. provided the exhaustion-specific gene-list analysis; S.X. performed western blot with the support of X.Y.; C.X. performed immunofluorescence with the support of S.B.; J.E.W. and O.K. provided support for in vitro culture conditions; A.-C.H. J.E.W. and S.F.N. made key editorial contributions to the manuscript; and Z. Chen, Z.J. and E.J.W. wrote the manuscript. E.J.W. has consulting agreements with and/or is on the scientific advisory board for Merck, Roche, Pieris, Elstar, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. has a patent licensing agreement on the PD-1 pathway with Roche/Genentech. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = nov,
day = "19",
doi = "10.1016/j.immuni.2019.09.013",
language = "English (US)",
volume = "51",
pages = "840--855.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Cell Press",
number = "5",
}