임세진 (Emory University School of Medicine)

한빛사논문

조회4,045

Emory University School of Medicine

Nature, 537, 417-421 (15 September 2016) | doi:10.1038/nature19330 Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy

Abstract

Se Jin Im¹, Masao Hashimoto¹, Michael Y. Gerner^2,3, Junghwa Lee¹, Haydn T. Kissick^1,4, Matheus C. Burger⁵, Qiang Shan⁶, J. Scott Hale¹, Judong Lee¹, Tahseen H. Nasti¹, Arlene H. Sharpe^7,8, Gordon J. Freeman⁹, Ronald N. Germain², Helder I. Nakaya⁵, Hai-Hui Xue^6,10 & Rafi Ahmed¹¹Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. ²Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-0421, USA. ³Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98109, USA. ⁴Department of Urology, Emory University School of Medicine, Atlanta, Georgia 30322, USA. ⁵School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508, Brazil. ⁶Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. ⁷Department of Microbiology and Immunology, Harvard Medical School, Boston, Massachusetts 02115, USA. ⁸Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 02115, USA. ⁹Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ¹⁰Interdisciplinary Immunology Graduate Program, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

Correspondence to : Rafi Ahmed

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^{1, 2, 3, 4}. 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 (TFH) cells, CD8⁺ T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4⁺ TH1 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.

논문정보

형식Research article
게재일2016년 09월 (BRIC 등록일 2016-09-23)
연구진국외 연구진
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