1. Strength of PD-1 signaling differentially affects T-cell effector functions.
- Author
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Wei F, Zhong S, Ma Z, Kong H, Medvec A, Ahmed R, Freeman GJ, Krogsgaard M, and Riley JL
- Subjects
- Calcium Signaling immunology, Cells, Cultured, Chemokine CCL4 biosynthesis, Cytotoxicity, Immunologic, HIV-1 immunology, Humans, Interferon-gamma biosynthesis, Interleukin-2 metabolism, Models, Immunological, Programmed Cell Death 1 Receptor chemistry, Receptors, Antigen, T-Cell, alpha-beta metabolism, Receptors, Antigen, T-Cell, alpha-beta physiology, T-Lymphocytes cytology, Tumor Necrosis Factor-alpha metabolism, Programmed Cell Death 1 Receptor physiology, Signal Transduction immunology, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
High surface expression of programmed death 1 (PD-1) is associated with T-cell exhaustion; however, the relationship between PD-1 expression and T-cell dysfunction has not been delineated. We developed a model to study PD-1 signaling in primary human T cells to study how PD-1 expression affected T-cell function. By determining the number of T-cell receptor/peptide-MHC complexes needed to initiate a Ca(2+) flux, we found that PD-1 ligation dramatically shifts the dose-response curve, making T cells much less sensitive to T-cell receptor-generated signals. Importantly, other T-cell functions were differentially sensitive to PD-1 expression. We observed that high levels of PD-1 expression were required to inhibit macrophage inflammatory protein 1 beta production, lower levels were required to block cytotoxicity and IFN-γ production, and very low levels of PD-1 expression could inhibit TNF-α and IL-2 production as well as T-cell expansion. These findings provide insight into the role of PD-1 expression in enforcing T-cell exhaustion and the therapeutic potential of PD-1 blockade.
- Published
- 2013
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