Antigen-specific targeting of CD4 T cells reveals distinct roles of higher and lower affinity self-reactive TCRs during autoimmunity

Higher and lower affinity self-reactive CD4 T cells are seen 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. The original MOG35-55 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.