Loss of CNS IL-2 gene expression modifies brain T lymphocyte trafficking: Response of normal versus autoreactive Treg-deficient T cells

Emerging data from our lab and others suggested that dysregulation of the brain's endogenous neuroimmunological milieu may occur with the loss of brain IL-2 gene expression and be involved in initiating processes that lead to CNS autoimmunity. We sought to test our working hypothesis that IL-2 deficiency induces endogenous changes in the CNS that play a key role in eliciting T cell homing into the brain. To accomplish this goal, we used an experimental approach that combined mouse congenic breeding and immune reconstitution. In congenic mice without brain IL-2 (two IL-2 KO alleles) that were reconstituted with a normal wild-type immune system, the loss of brain IL-2 doubled the number of T cells that trafficked into the brain in all regions quantified (hippocampus, septum, and cerebellum) compared to mice with two wild-type brain IL-2 alleles and a wild-type peripheral immune system. Congenic mice with normal brain IL-2 (two wild-type IL-2 alleles) that were immune reconstituted with autoreactive Treg-deficient T cells from IL-2 KO mice developed the expected peripheral autoimmunity (splenomegaly) and had a comparable doubling of T cell trafficking into the hippocampus and septum, whereas they exhibited an additional twofold proclivity for the cerebellum over the septohippocampal regions. Unlike brain trafficking of wild-type T cells, the increased homing of IL-2 KO T cells to the cerebellum was independent of brain IL-2 gene expression. These findings demonstrate that brain IL-2 deficiency induces endogenous CNS changes that may lead to the development of brain autoimmunity, and that autoreactive Treg-deficient IL-2 KO T cells trafficking to the brain could have a proclivity to induce cerebellar neuropathology.

► IL-2 deficiency elicits T cell homing into the brain.
► The loss of brain IL-2 with a normal wild-type immune system doubled the number of T cells that trafficked into the brain in all regions.
► Normal brain IL-2 with autoreactive Treg-deficient T cells had a comparable doubling of T cell trafficking into the hippocampus and septum.
► Unlike brain trafficking of wild-type T cells, the increased homing of IL-2 KO T cells to the cerebellum was independent of brain IL-2 gene expression.
► Findings demonstrate that brain IL-2 deficiency induces endogenous CNS changes.