About: 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. © 2011 Wiley‐Liss, Inc.   Goto Sponge  NotDistinct  Permalink

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  • 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. © 2011 Wiley‐Liss, Inc.
Subject
  • Immunology
  • Immune system
  • Central nervous system
  • Glial cells
  • Animal anatomy
  • Clusters of differentiation
  • Epstein–Barr virus-associated diseases
  • Human cells
  • Membrane biology
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