Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection
| Autor: | Pablo Penaloza-MacMaster, Shu Yang, Erin E. West, Andreas Wieland, Koichi Araki, Smita S. Iyer, Bogumila T. Konieczny, Gordon J. Freeman, Leigh A. O’Mara, Alexander Y. Rudensky, Rafi Ahmed, Alice O. Kamphorst, Arlene H. Sharpe |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
CD4-Positive T-Lymphocytes
T cell Immunology Programmed Cell Death 1 Receptor chemical and pharmacologic phenomena Mice Transgenic Biology CD8-Positive T-Lymphocytes Lymphocytic Choriomeningitis Lymphocyte Activation T-Lymphocytes Regulatory Article Lymphocyte Depletion 03 medical and health sciences Interleukin 21 Mice 0302 clinical medicine medicine Immunology and Allergy Cytotoxic T cell Animals Lymphocytic choriomeningitis virus IL-2 receptor 030304 developmental biology 0303 health sciences CD40 ZAP70 CD28 hemic and immune systems Dendritic Cells Natural killer T cell 3. Good health Up-Regulation Mice Inbred C57BL medicine.anatomical_structure Chronic Disease biology.protein 030215 immunology |
| Zdroj: | The Journal of Experimental Medicine |
| ISSN: | 1540-9538 0022-1007 |
| Popis: | T reg cells effectively maintain CD8 T cell exhaustion during chronic LCMV infection, but blockade of PD-1 is critical for elimination of infected cells. Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells. |
| Databáze: | OpenAIRE |
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