VLA4 expression by B cells enables B cell-restricted antigen presentation to support CD4 T cell driven central nervous system autoimmunity
JOURNAL OF IMMUNOLOGY(2018)
Abstract
Abstract Clonal expansion along with immunoglobulin (Ig) class-switching and secretion result from B cell antigen presentation to cognate CD4 T cells. The presence of oligoclonal Ig in the cerebrospinal fluid of most patients with multiple sclerosis raises the important question of where cognate B:T cell interactions occurs during disease. Previously we showed that increasing the frequency of MOG-specific B cells is sufficient to drive EAE in mice expressing MHCII solely by B cells. We have now established a system in which EAE reliably occurs upon expression of MHCII using Tamoxifen-induced temporal regulation in MOG-specific B cells. While B cells express MHCII in the central nervous system (CNS) in these models, whether or not B cells acquire and present antigen in the CNS compartment is unknown. Large clusters of B cells rapidly formed in the subarachnoid space of the spinal cord during EAE in our model, suggesting homing to the CNS is important for antigen presentation. Genetic regulation of B cell MOG-specificity and expression of MHCII and Very Late Antigen-4 (VLA-4) was used to determine the dependence of passive EAE susceptibility on B cell access to the CNS. Mice in which VLA-4 expression was abrogated simultaneously with MHCII expression by MOG-specific B cells were subjected to passive EAE. Disease exclusively mediated by B cell antigen presentation was dependent on VLA-4 expression by B cells. MOG-specific CD4 T cell hybridomas did not detect endogenous MOG presented by B cells harvested from the periphery of mice prior to the onset of disease. Taken together, our findings indicate that B cells require access to CNS myelin targets in order to propagate antigen-specific CD4 T cell-dependent neuro-inflammation.
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