![]() ![]() For example, multiple sclerosis (MS) is widely believed to be caused by myelin-specific autoreactive CD4 + T cells ( 1– 3). 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.Īutoimmunity is thought to arise from self-antigen–reactive effector T cells possibly induced by impaired regulatory T cell (T reg) function or cross-reactivity to foreign antigens. 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. Our original MOG 35–55 pMHCII-CAR, which targeted only higher-affinity TCRs, could prevent the induction of experimental autoimmune encephalomyelitis (EAE). Integration of improvements in CAR engineering with TCR repertoire analysis was critical for interrogating in vivo the role of TCR affinity in autoimmunity. ![]() We addressed this question using peptide-MHCII chimeric antigen receptor (pMHCII-CAR) T cells to specifically deplete peptide-reactive T cells in mice. Both higher- and lower-affinity self-reactive CD4 + T cells are expanded in autoimmunity however, their individual contribution to disease remains unclear.
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