Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
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 im...
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Published in | Nature (London) Vol. 537; no. 7620; pp. 417 - 421 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Nature Publishing Group
15.09.2016
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0028-0836 1476-4687 1476-4687 |
DOI: | 10.1038/nature19330 |