title: Loss of CNS IL-2 gene expression modifies brain T lymphocyte trafficking: response of normal versus autoreactive Treg-deficient T cells.
abstract: 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.
authors.affiliation: Department of Psychiatry, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Huang
authors.forename: Danielle
authors.initials: D
authors.lastname: Meola
authors.forename: John M
authors.initials: JM
authors.lastname: Petitto
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002531:Cerebellum / Q000276:immunology / Q000502:physiology*; D015870:Gene Expression / Q000502:physiology*; D006624:Hippocampus / Q000276:immunology / Q000502:physiology*; D007376:Interleukin-2 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015213:Neuroimmunomodulation / Q000235:genetics / Q000502:physiology; D020665:Septum of Brain / Q000276:immunology / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D007376:Interleukin-2