Traumatic Injury and the Presence of Antigen Differentially Contribute to T-Cell Recruitment in the CNS

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Abstract
T-cell recruitment into the brain is critical in inflammatory and autoimmune diseases of the CNS. We use intracerebral antigen microinjection and tetramer technology to track antigen-specific CD8+T-cells in the CNS and to clarify the contribution of antigen deposition or traumatic injury to the accumulation of T-cells in the brain. We demonstrate that, after intracerebral microinjection of ovalbumin, ovalbumin-specific CD8+T-cells expand systemically and then migrate into the brain where they complete additional proliferation cycles. T-cells in the brain are activated and respond toin vitrosecondary antigen challenge. CD8+T-cells accumulate and persist in sites of antigen in the brain without replenishment from the periphery. Persistent survival of CD8+T-cells at sites of cognate antigen is significantly reduced by blocking CD154 molecules. A small traumatic injury itself does not lead to recruitment of CD8+T-cells into the brain but attracts activated antigen-specific CD8+T-cells from cognate antigen injection sites. This process is presumably antigen independent and cannot be inhibited by blocking CD154 molecules. These data show that activated antigen-specific CD8+T-cells accumulate in the CNS at both cognate antigen-containing and traumatic injury sites after intracerebral antigen delivery. The accumulation of activated antigen-specific T-cells at traumatic injury sites, in addition to antigen-containing areas, could amplify local inflammatory processes in the CNS. Combination therapies in neuroinflammatory diseases to block both of these processes should be considered.