High affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells.

Autor:	Cochrane RW; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Robino RA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Granger B; Bioinformatics Core, Medical University of South Carolina, Charleston, SC, USA., Allen E; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Vaena S; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Romeo MJ; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., de Cubas AA; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA., Berto S; Bioinformatics Core, Medical University of South Carolina, Charleston, SC, USA.; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA., Ferreira LMR; Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA.; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Apr 01. Date of Electronic Publication: 2024 Apr 01.
DOI:	10.1101/2024.03.31.587467
Abstrakt:	Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T-cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28 activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3 + CAR Tregs uniquely acquiring CD40L surface expression and producing IFNγ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy. Competing Interests: DECLARATION OF INTERESTS L.M.R.F. is the inventor on a provisional patent based on results from this work, an inventor on provisional and licensed patents on engineered immune cells, and a consultant with Guidepoint Global. The other authors declare no conflicts of interest.
Databáze:	MEDLINE
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