Bone Marrow T Cell Sequestration As A Novel Mode Of Cns Immune Privilege

Abstract The central nervous system (CNS), although a site of relative immune “privilege,” is continuously monitored by immune cells. The CNS must possess means for limiting excess inflammation that can otherwise cause irreparable damage or death. Recently, we characterized a unique mode of cancer-induced immunosuppression whereby T cells become sequestered in high numbers in the bone marrow (BM) of humans and mice with intracranial tumors. Sequestration of T cells is mediated in part by the loss of sphingosine-1-phosphate receptor 1 (S1P1) from the T cell surface. Interestingly, this phenomenon occurs only when tumors are located intracranially, but not peripherally. This suggests that sequestration is not mediated by brain tumors themselves, but instead represents tumors usurping of a novel mechanism for CNS immune privilege designed to limit T-cell access to the CNS. Consequently, we investigated whether BM T cell sequestration occurs in other CNS disorders, such as stroke. In a murine model of stroke, immune alterations recapitulated those observed in intracranial tumors. These changes include severe but transient lymphopenia, lymphoid organ shrinkage, and BM T cell sequestration. As with intracranial tumors, BM T cell sequestration was mediated by loss of surface S1P1 on T cells. A mechanistic understanding of CNS-driven BM T cell sequestration will enable the development of novel therapeutics to limit neuroinflammation and damage in the context of CNS pathologies.