Antigen-specific depletion of CD4 + T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity

• Published in: Science immunology Vol. 7; no. 76; p. eabo0777
• Main Authors: Yi, Jaeu, Miller, Aidan T, Archambault, Angela S, Jones, Andrew J, Bradstreet, Tara R, Bandla, Sravanthi, Hsu, Yu-Sung, Edelson, Brian T, Zhou, You W, Fremont, Daved H, Egawa, Takeshi, Singh, Nathan, Wu, Gregory F, Hsieh, Chyi-Song
• Format: Journal Article
• Language: English
• Published: United States 14.10.2022
• Subjects: Animals; Antigens; Autoimmunity; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Mice; Peptides; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen - genetics
• ISSN: 2470-9468
• DOI: 10.1126/sciimmunol.abo0777

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 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.