1. The majority of infiltrating CD8 T lymphocytes in multiple sclerosis lesions is insensitive to enhanced PD-L1 levels on CNS cells.
- Author
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Pittet CL, Newcombe J, Antel JP, and Arbour N
- Subjects
- Antigens, CD genetics, B7-H1 Antigen, CD8-Positive T-Lymphocytes immunology, Cytokines immunology, Cytokines metabolism, Flow Cytometry, Humans, Immunohistochemistry, Multiple Sclerosis immunology, Neuroglia immunology, Neuroglia metabolism, Neurons immunology, Neurons metabolism, Reverse Transcriptase Polymerase Chain Reaction, Antigens, CD metabolism, CD8-Positive T-Lymphocytes metabolism, Cytokines pharmacology, Multiple Sclerosis metabolism, Neuroglia drug effects, Neurons drug effects
- Abstract
Central nervous system (CNS) cells locally modulate immune responses using numerous molecules that are not fully elucidated. Engagement of programmed death-1 (PD-1), expressed on activated T cells, by its ligands (PD-L1 or PD-L2) suppresses T-cell responses. Enhanced CNS PD-1 and PD-L1 expression has been documented in inflammatory murine models; however, human CNS data are still incomplete. We determined that human primary cultures of astrocytes, microglia, oligodendrocytes, or neurons expressed low or undetectable PD-L1 under basal conditions, but inflammatory cytokines significantly induced such expression, especially on astrocytes and microglia. Blocking PD-L1 expression in astrocytes using specific siRNA led to significantly increased CD8 T-cell responses (proliferation, cytokines, lytic enzyme). Thus, our results establish that inflamed human glial cells can express sufficient and functional PD-L1 to inhibit CD8 T cell responses. Extensive immunohistochemical analysis of postmortem brain tissues demonstrated a significantly greater PD-L1 expression in multiple sclerosis (MS) lesions compared with control tissues, which colocalized with astrocyte or microglia/macrophage cell markers. However, more than half of infiltrating CD8 T lymphocytes in MS lesions did not express PD-1, the cognate receptor. Thus, our results demonstrate that inflamed human CNS cells such as in MS lesions express significantly elevated PD-L1, providing a means to reduce CD8 T cell responses, but most of these infiltrating immune cells are devoid of PD-1 and thus insensitive to PD-L1/L2. Strategies aimed at inducing PD-1 on deleterious activated human CD8 T cells that are devoid of this receptor could provide therapeutic benefits since PD-L1 is already increased in the target organ., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2011
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