Nervous system control and regulation of the immune system following neurological insults

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Suppression of the immune system following damage to the central nervous system (CNS) is a common feature of neurological diseases as diverse as stroke, traumatic brain injury (TBI), and glioblastoma (GBM). This immunosuppression causes mortality and leads to the failure of immune-modulating therapies. The underlying mechanisms of systemic immunosuppression following neurological insults remain largely unknown. In this proposal, we focus on the thymus, the primary immune organ responsible for T cell development in children and adults. We tested thymic function following various neurological insults, including viral infections of the CNS, tumors, sterile inflammation, physical injury, and seizure activity. All insults resulted in significant thymic involution that was reversible upon clearance of the injury. Importantly, thymic involution did not occur following peripheral insults. Using parabiosis, we found that thymic involution was transferable from glioma- bearing to non-tumor-bearing parabionts demonstrating the crucial role of serum-derived soluble factors in mediating thymic involution. Specifically, serum-derived molecules with molecular weights (MW) larger than 300 kDa were deemed immunosuppressive. Interestingly, the thymus is heavily innervated by the CNS, yet the role of this innervation during neurological injuries and immunosuppression remains unknown. We demonstrated, for the first time, that the thymus is heavily innervated by both extrinsic neurons (cell bodies outside of the thymus), and intrinsic neurons (cell bodies within the thymus) using rabies virus neurotracers. In short, the multifaceted immunosuppression following neurological insults alters immune homeostasis in the thymus, bone marrow, and the spleen. The extents to which these alterations in the immune organs induce transient or long-lasting immunological defects remain understudied. Thymic involution, presence of immunosuppressive factors in serum, changes within the bone marrow niche, and long-lasting immunological defects together account, at least in part, for immune deficiencies observed following neurologic injuries. Based on these data, we hypothesized that following neurological insults the brain suppresses the immune system both systemically and locally through soluble factors and innervation. This in turn alters the immune repertoire and affects long-term immunity. This hypothesis will be tested in the following three aims: Aim1: To determine the molecular identity of serum-derived immunosuppressive factors during neurological insults; Aim 2: To determine the function of thymic innervation at baseline and during neurological insults; Aim 3: To determine transient and long-lasting functional consequences of immunosuppression on the immune system following neurological injuries. Successful completion of these aims will significantly impact understanding of immunosuppression and nervous control of the immune system during neurological injuries and will help us develop new therapeutics to combat immunosuppression in a large cohort of patients with acute and chronic neurological traumas.