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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
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Nature (Aug 2 2016)
"We have defined a PD-1+ virus-specific CD8+ T cell population in chronically infected mice that is characterized by a unique gene signature that has similarities to CD4+ Tfh cells, CD8 memory precursor cells and hematopoietic stem cell progenitors. This unique transcriptional program may represent a specific adaptation of CD8+ T cells to chronic antigenic stimulation. It will be of interest to determine if a similar adaptation occurs during autoimmunity and cancer. The identification of such CD8+ T cells in cancer will be of special relevance since our studies in chronic LCMV infection have shown that it is these CD8+ T cells that selectively proliferate after PD-1 blockade. PD-1 directed immunotherapy is now one of the most promising approaches for treatment of several different types of cancers and is an approved drug for melanoma, lung cancer and bladder cancer. Our study defining the phenotype, gene expression program and biological properties of the CD8+ T cells that respond to PD-1 blockade should be value in optimizing PD-1 targeted therapies."

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 receptor1-4. 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 the 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 at the same time also expressed several co-stimulatory molecules such as ICOS, OX-40 and CD28. This CD8+ T cell subset was characterized by a unique gene signature that was related to CD4+ T follicular helper (Tfh) cells, CD8+ T cell memory precursors and hematopoietic stem cell progenitors, but that was distinct from CD4+ Th1 cells and CD8+ terminal effectors. This CD8+ T cell population was only found in lymphoid tissues and resided predominantly in the T cell zones along with naive CD8+ T cells. These PD-1+CD8+ T cells were stem cell-like 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. Importantly, the transcription factor TCF1 played 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 towards optimizing PD-1-directed immunotherapy in chronic infections and cancer.
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