Novel immune therapy to promote functional recovery after traumatic brain injury

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Traumatic brain injury (TBI) leads to high mortality and morbidity amongst veterans and civilians. There is an urgent unmet need for therapies to alleviate the long-term neurological deficits after TBI. Innate (microglia and macrophages) and adaptive (T and B lymphocytes) immune cells play critical roles in neuroinflammation, injury progression, and brain repair. Microglia/macrophages are highly plastic cells that execute both beneficial and detrimental functions after injury. Our previous studies highlight a shift of microglia/macrophages at the chronic stages of TBI toward a neurotoxic, pro-inflammatory phenotype that impairs tissue preservation and brain repair. Therefore, identification of mechanisms underlying anti-inflammatory/reparative microglia/macrophage responses may reveal novel therapeutic targets to foster a microenvironment permissive for brain repair and long-term recovery after TBI. CD4+CD25+ regulatory T cells (Tregs) are a specialized subpopulation of T cells known to alleviate inflammation. We reported that Tregs exerted neuroprotection by targeting inflammatory dysregulation in stroke. The effects of Tregs in TBI have not been appreciated until recently, and their mechanism of action is unknown. We recently in vitro study show that Tregs activated by brain injury stimulate microglial polarization toward an anti-inflammatory/reparative phenotype, which in turn promotes oligodendrocyte differentiation and maturation. Using the controlled cortical impact model of TBI, we have obtained in vivo data showing that: 1) Selective Treg depletion further deteriorates long-term sensorimotor and cognitive functional deficits and exacerbates brain lesions in both white matter and gray matter up to 21 days after TBI. 2) Treg-depleted mice display worse cerebral inflammation and more aggressive pro-inflammatory microglia/macrophage responses after TBI. 3) In contrast, boosting Tregs using an IL-2/IL-2 antibody complex (IL-2/IL-2Ab) significantly reduces brain injury and improves neurological functions after TBI. Given these new observations, the proposed studies will be the first to test the mechanistic hypothesis that Tregs improve brain repair and promote long-term recovery after TBI by polarizing microglia/macrophages toward an inflammation-resolving and reparative phenotype. Three Aims will be completed in a systematic fashion. Aim 1. Test if Tregs improve gray and white matter integrity and enhance long-term functional recovery after TBI. Aim 2. Test if Tregs shift microglia/macrophages toward an inflammation-resolving and tissue-reparative phenotype after TBI. Aim 3. Test if in vivo expansion of Tregs with IL-2/IL-2Ab treatment post-TBI reduces brain lesions and improves long-term neurological recovery. This study will be the first to mechanistically define the role of Tregs in regulating microglia/macrophage responses after TBI and to test the therapeutic potential of IL-2/IL-2Ab in TBI. If successful, these studies may reveal a new therapeutic horizon for TBI and other neurological disorders that involve persistent inflammation and diverse microglia/macrophages responses.