Details

Autor(en) / Beteiligte

• Im, Se Jin
• Hashimoto, Masao
• Gerner, Michael Y
• Lee, Junghwa
• Kissick, Haydn T
• Burger, Matheus C
• Shan, Qiang
• Hale, J Scott
• Lee, Judong
• Nasti, Tahseen H
• Sharpe, Arlene H
• Freeman, Gordon J
• Germain, Ronald N
• Nakaya, Helder I
• Xue, Hai-Hui
• Ahmed, Rafi

Titel

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

Ist Teil von

• Nature (London), 2016-09, Vol.537 (7620), p.417-421

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 ) cells, CD8 T cell memory precursors and haematopoietic stem cell progenitors, but that was distinct from that of CD4 T 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.