CNS‐infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection‐induced neuropathic pain

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Abstract
We previously reported leukocytic infiltration into the lumbar spinal cord in a rodent spinal nerve L5 transection (L5Tx) neuropathic pain model. Here, we further investigated the role of infiltrating T lymphocytes in the etiology of persistent pain following L5Tx. T lymphocyte‐deficient nude mice showed no evident mechanical hypersensitivity after day 3 of L5Tx compared to wild‐type BALB/c mice. Through FACS analysis, we determined that significant leukocytic infiltration (CD45hi) into the lumbar spinal cord peaked at day 7 post L5Tx. These infiltrating leukocytes contained predominantly CD4+ but not CD8+ T lymphocytes. B lymphocytes, natural killer cells and macrophages were not detected at day 7 post L5Tx. No differences in the activation of peripheral CD4+ T lymphocytes were detected in either the spleen or lumbar lymph nodes between L5Tx and sham surgery groups. Further, CD4 KO mice displayed significantly decreased mechanical hypersensitivity after day 7 of L5Tx, and adoptive transfer of CD4+ leukocytes reversed this effect. Decreased immunoreactivity of glial fibrillary acidic protein observed in CD4 KO mice post L5Tx indicated possible T lymphocyte‐glial interactions. These results strongly support a contributing role of spinal cord‐infiltrating CD4+ T lymphocytes versus peripheral CD4+ T lymphocytes in the maintenance of nerve injury‐induced neuropathic pain.