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Chronic progressive neuroinflammatory disease multiple sclerosis (MS) is characterized by loss of neuronal functions
resulting from axonal degeneration and demyelination. Infiltration of myelinolytic CD4+ T lymphocytes is one of the major
pathophysiological events leading to neurodegeneration in autoimmune model of MS, experimental autoimmune encephalomyelitis. By
contrast, CNS-infiltrating CD4+ T cells protect the CNS from demyelination in the Mouse Hepatitis Virus (MHV-A59)-induced
neuroinflammatory model of MS. The absence of CD4+ T cells significantly affects the microglial activation and homeostatic response.
Typically, M2 microglial activation fails to resolve during the chronic infection, rendering mice more susceptible to demyelination and
axonal bulbar vacuolation. The current study investigated the CD4-microglia nexus at the molecular level using CD40L-/- mice. Results
showed that the absence of CD40L renders mice highly susceptible to MHV infection due to reduced microglia/macrophage activation
during the acute phase of infection required to eliminate the virus. Effector CD4+ T recruitment to the CNS is significantly dampened,
and due to the impaired CD40-CD40L signaling in CD40L-/- mice, their priming is reduced substantially in the draining lymph nodes.
Moreover, CD40L-/- mice exhibited greater demyelination, axonal loss, and persistent poliomyelitis at the chronic phase of infection.
Together, these studies highlight that migration of peripheral T cells and their interaction with microglia via CD40-CD40L is essential to
eliminate the virus and provide long-term neuroprotection. |