@article {1051401,
	title = {Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy},
	journal = {Nature},
	volume = {537},
	number = {7620},
	year = {2016},
	month = {2016 09 15},
	pages = {417-421},
	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 (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.},
	keywords = {Animals, Antigens, CD28, CD8-Positive T-Lymphocytes, Cell Differentiation, Cell Proliferation, Cell Self Renewal, Female, Hematopoietic Stem Cells, Hepatocyte Nuclear Factor 1-alpha, Immunotherapy, Inducible T-Cell Co-Stimulator Protein, Lymphocytic Choriomeningitis, Lymphocytic choriomeningitis virus, Mice, Programmed Cell Death 1 Receptor, T-Lymphocyte Subsets, T-Lymphocytes, Helper-Inducer},
	issn = {1476-4687},
	doi = {10.1038/nature19330},
	author = {Im, Se Jin and Hashimoto, Masao and Gerner, Michael Y and Lee, Junghwa and Kissick, Haydn T and Burger, Matheus C and Shan, Qiang and Hale, J Scott and Lee, Judong and Nasti, Tahseen H and Sharpe, Arlene H and Freeman, Gordon J and Germain, Ronald N and Nakaya, Helder I and Xue, Hai-Hui and Ahmed, Rafi}
}
