Shared and distinct biological circuits in effector, memory and exhausted CD8(+) T cells revealed by temporal single-cell transcriptomics and epigenetics

• Type of Material: Article
• Authors: Josephine R. Giles, University of Pennsylvania; Shin Foong Ngiow, University of Pennsylvania; Sasikanth Manne, University of Pennsylvania; Amy E. Baxter, University of Pennsylvania; Omar Khan, University of Pennsylvania; Ping Wang, University of Pennsylvania; Ryan Staupe, University of Pennsylvania; Mohamed Abdel Hakeem, Emory University; Hua Huang, University of Pennsylvania; Divij Mathew, University of Pennsylvania; Mark M. Painter, University of Pennsylvania; Jennifer E. Wu, University of Pennsylvania; Yinghui Huang, University of Pennsylvania; Rishi R. Goel, University of Pennsylvania; Patrick K. Yan, University of Pennsylvania; Giorgos C. Karakousis, University of Pennsylvania; Xiaowei Xu, University of Pennsylvania; Tara C. Mitchell, University of Pennsylvania; Alexander C. Huang, University of Pennsylvania; E. John Wherry, University of Pennsylvania
• Language: English
• Date: 2022-10-21
• Publisher: NATURE PORTFOLIO
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-022-01338-4
• Title of Journal or Parent Work: NATURE IMMUNOLOGY
• Volume: 23
• Issue: 11
• Start Page: 1600
• End Page: +
• Grant/Funding Information: This work was supported by T32 CA009140 and a Cancer Research Institute-Mark Foundation Fellowship (to J.G.), by the Parker Institute for Cancer Immunotherapy and Stand Up to Cancer and National Institutes of Health (NIH) grants AI155577, AI149680, AI108545, AI082630, DK127768 and CA210944 (to E.J.W.). Work in the Wherry laboratory is supported by the Parker Institute for Cancer Immunotherapy. S.F.N. was supported by an Australia NHMRC C.J. Martin Fellowship (GNT1111469) and the Mark Foundation Momentum Fellowship. O.K. was supported by an NIAID F30 fellowship (F30AI129263). D.M. was supported through The American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists. J.E.W. was supported by a PICI Scholar award. Y.J.H. was supported by a National Science Foundation graduate research fellowship. A.C.H. was supported by NIH grant K08-CA230157, the Damon Runyon Clinical Investigator Award, Doris Duke Clinical Scientist Development Award, W. W. Smith Charitable Trust Award, the Tara Miller Foundation and P50 CA174523. The melanoma clinical trial was supported by SPORE grant P50CA261608.
• Keywords: Science & Technology; LANDSCAPE; ZEB2; COOPERATE; RECEPTORS; Life Sciences & Biomedicine; PROGRAMS; CHRONIC INFECTION; TERMINAL DIFFERENTIATION; Immunology; QUIESCENCE; SELF-RENEWAL; EXPRESSION
• Research Categories: Health Sciences, Immunology

Abstract

Naïve CD8+ T cells can differentiate into effector (Teff), memory (Tmem) or exhausted (Tex) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within Teff, Tmem and Tex populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of Tex cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1+ stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of Tex subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the Tex population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8+ T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.