Defining CD8(+) T cells that provide the proliferative burst after PD-1 therapy

• Type of Material: Article
• Authors: Sejin Im, Emory University; Masao Hashimoto, Emory University; Michael Y. Gerner, National Institute of Allergy and Infectious Diseases; Junghwa Lee, Emory University; Haydn Kissick, Emory University; Matheus C. Urger, University of Sao Paulo; Qiang Shan, University of Iowa; J. Scott Hale, Emory University; Judong Lee, Emory University; Tahseen H. Nasti, Emory University; Arlene H. Sharpe, Harvard Medical School; Gordon J. Freeman, Harvard Medical School; Ronald N. Germain, National Institute of Allergy and Infectious Diseases; Helder Nakaya, Emory University; Hai-Hui Xue, University of Iowa; Rafi Ahmed, Emory University
• Language: English
• Date: 2016-09-15
• Publisher: Nature Publishing Group
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016 Macmillan Publishers Limited, part of Springer Nature.
• Final Published Version (URL): http://dx.doi.org/10.1038/nature19330
• Title of Journal or Parent Work: Nature
• ISSN: 0028-0836
• Volume: 537
• Issue: 7620
• Start Page: 417
• End Page: +
• Grant/Funding Information: This work was supported by National Institutes of Health grants R01 AI30048 (R.A.), P01 AI056299 (R.A. and A.H.S.), R01 AI112579 (H.H.X.) and R01 AI121080 (H.H.X) and also by the Intramural Research Program of NIAID, NIH (R.N.G. and M.Y.G.).; H.T.K. is supported by funding from the Prostate Cancer Foundation and Swim Across America.; H.I.N. receives a CNPq research fellowship.
• Keywords: TRANSCRIPTION FACTOR; Multidisciplinary Sciences; LYMPHOID ORGANS; DIFFERENTIATION; PERSISTENCE; LYMPHOCYTIC CHORIOMENINGITIS VIRUS; FH; EXHAUSTION; Science & Technology - Other Topics; Science & Technology; EFFECTOR; CHRONIC VIRAL-INFECTION; MEMORY
• Research Categories: Health Sciences, Immunology; Health Sciences, Pharmacology

Abstract

Chronic viral infections are characterized by a state of CD8+ T-cell dysfunction that is associated with expression of the programmed cell death 1 (PD-1) inhibitory receptor. A better understanding of the mechanisms that regulate CD8+ T-cell responses during chronic infection is required to improve immunotherapies that restore function in exhausted CD8+ T cells. Here we identify a population of virus-specific CD8+ T cells that proliferate after blockade of the PD-1 inhibitory pathway in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). These LCMV-specific CD8+ T cells expressed the PD-1 inhibitory receptor, but also expressed several costimulatory molecules such as ICOS and CD28. This CD8+ T-cell subset was characterized by a unique gene signature that was related to that of CD4+ T follicular helper (T FH) cells, CD8+ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4+ T H 1 cells and CD8+ terminal effectors. This CD8+ T-cell population was found only in lymphoid tissues and resided predominantly in the T-cell zones along with naive CD8+ T cells. These PD-1+ CD8+ T cells resembled stem cells during chronic LCMV infection, undergoing self-renewal and also differentiating into the terminally exhausted CD8+ T cells that were present in both lymphoid and non-lymphoid tissues. The proliferative burst after PD-1 blockade came almost exclusively from this CD8+ T-cell subset. Notably, the transcription factor TCF1 had a cell-intrinsic and essential role in the generation of this CD8+ T-cell subset. These findings provide a better understanding of T-cell exhaustion and have implications in the optimization of PD-1-directed immunotherapy in chronic infections and cancer.