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Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy
Se Jin Im1, Masao Hashimoto1, Michael Y Gerner2,3
1Emory Vaccine Center and Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Insights
Researchers identified a novel CD8+ T cell subset resembling stem cells during chronic viral infections. Blocking PD-1 (programmed cell death 1) pathway revitalized these cells, offering new immunotherapy targets for chronic infections and cancer.
Area of Science:
- Immunology
- Virology
- Cell Biology
Background:
- Chronic viral infections induce CD8+ T-cell dysfunction, characterized by programmed cell death 1 (PD-1) receptor expression.
- Restoring function in exhausted CD8+ T cells is crucial for effective immunotherapies against chronic infections.
- Understanding the regulation of CD8+ T-cell responses during chronic infection is needed to improve existing treatments.
Purpose of the Study:
- To identify and characterize CD8+ T-cell populations involved in immune responses during chronic viral infections.
- To investigate the role of the PD-1 inhibitory pathway in regulating CD8+ T-cell function.
- To explore potential therapeutic strategies for enhancing anti-viral immunity.
Main Methods:
- Utilized a mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection.
- Analyzed virus-specific CD8+ T cells, including their gene expression and surface marker profiles.
- Investigated the effects of PD-1 pathway blockade on T-cell proliferation and function.
- Assessed the role of the transcription factor TCF1 in CD8+ T-cell subset generation.
Main Results:
- Identified a unique CD8+ T-cell subset expressing PD-1, ICOS, and CD28, with a gene signature resembling T follicular helper cells and memory precursors.
- This PD-1+ CD8+ T-cell population resides in lymphoid tissues, exhibits stem-like properties (self-renewal), and differentiates into terminally exhausted cells.
- PD-1 pathway blockade induced significant proliferation, primarily from this specific CD8+ T-cell subset.
- The transcription factor TCF1 is essential for the generation of this stem-like CD8+ T-cell population.
Conclusions:
- Discovered a novel, stem-like CD8+ T-cell subset crucial for maintaining T-cell responses during chronic viral infections.
- These findings elucidate mechanisms of T-cell exhaustion and highlight the potential of targeting PD-1 and TCF1 for immunotherapy.
- The results have significant implications for optimizing PD-1-directed immunotherapies in chronic infections and cancer.
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.
