Lymphopenia and bone marrow T cell sequestration accompanying stroke are mediated by T cell S1P1 loss

Abstract

Abstract Sequestration of T cells in bone marrow is a phenomenon recently characterized by our group in the setting of intracranial tumors, regardless of histology. It is accompanied by lymphopenia and lymphoid organ regression and is mediated by loss of S1P1 receptor from the T cell surface. We now reveal that this phenomenon is not unique to tumors, but accompanies additional intracranial pathologies, most notably stroke. In this study, blood, bone marrow, and spleens were collected from mice at day 2, 5, 7 or 14 following stroke via middle cerebral artery occlusion (MCAO) or sham surgery and analyzed by flow cytometry. T cell S1P1 levels were assessed, as were T cell counts in each compartment. S1P1 receptor stabilization was achieved with a knock-in model in which receptor internalization is inhibited. Following stroke, T cells accumulated in the bone marrow of injured mice. T cell numbers peaked at day 7 post-stroke before returning to normal by day 14. Bone marrow accumulation was accompanied by transient lymphopenia and splenic involution following stroke. T cells in the bone marrow yielded decreased levels of S1P1 on their surface. Conversely, mice with genetically stabilized T cell S1P1 protected against sequestration, lymphopenia, and splenic regression following stroke. In conclusion, bone marrow T cell sequestration occurs transiently following stroke and is mediated by the S1P-S1P1 axis. This may be prove an adaptive mechanism to limit intracranial inflammation following an initial insult. Better understanding of this phenomenon may uncover a novel mechanism of immune privilege and allow for therapeutic modulation in the setting of stroke, brain tumor, and other types of intracranial injury.