We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Antigen-specific depletion of CD4<sup>+</sup> T cells by CAR T cells reveals distinct roles of higher- and lower-affinity TCRs during autoimmunity.
- 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
- Abstract
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 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. Engineering CAR T cells to target autoimmunity: Autoimmune diseases including multiple sclerosis (MS) are driven by pathogenic CD4+ T cells that recognize self-antigens. Yi et al. engineered chimeric antigen receptor (CAR) T cells to recognize and kill self-reactive T cells by introducing a peptide-MHCII (pMHCII) domain. Their original pMHCII-CAR design efficiently deleted T cells bearing a higher-affinity T cell receptor, whereas further modifications to enhance pMHCII stability and in vivo survival enabled simultaneous targeting of lower-affinity T cells. In a mouse experimental autoimmune encephalomyelitis model of MS-like disease, deletion of higher-affinity T cells was sufficient to prevent disease onset, whereas targeting lower-affinity T cells was necessary to reverse ongoing disease. These findings highlight strategies for designing CAR T cells to target distinct stages of autoimmune disease.
- Publication
Science Immunology, 2022, Vol 7, Issue 76, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.abo0777