SignificanceA distinct murine model of multiple sclerosis used to examine factors involved in ectopic lymphoid tissue formation during central nervous system autoimmunity reveals that infiltration and aggregation of B cells within the leptomeninges is dependent upon B cell expression of VLA-4 and is preceded by neutrophil migration. This finding establishes the early mechanisms involved in the establishment of chronic inflammatory changes within the meninges during autoimmune inflammation that promote the formation of ectopic lymphoid tissue associated with disease progression and disability in multiple sclerosis.
Both higher- and lower-affinity self-reactive CD4
+
T cells are expanded in autoimmunity; however, their individual contribution to disease remains unclear. We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity. Our original MOG
35–55
pMHCII-CAR, which targeted only higher-affinity TCRs, could prevent the induction of experimental autoimmune encephalomyelitis (EAE). However, pMHCII-CAR enhancements to pMHCII stability, as well as increased survivability via overexpression of a dominant-negative Fas, were required to target lower-affinity MOG-specific T cells and reverse ongoing clinical EAE. Thus, these data suggest a model in which higher-affinity autoreactive T cells are required to provide the “activation energy” for initiating neuroinflammatory injury, but lower-affinity cells are sufficient to maintain ongoing disease.
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