The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28.

Citation
Muller, Y. D., et al. “The Cd28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With Cd28.”. Frontiers In Immunology, p. 639818.
Center UCSF
Author Yannick D Muller, Duy P Nguyen, Leonardo M R Ferreira, Patrick Ho, Caroline Raffin, Roxxana Valeria Beltran Valencia, Zion Congrave-Wilson, Theodore L Roth, Justin Eyquem, Frederic Van Gool, Alexander Marson, Laurent Perez, James A Wells, Jeffrey A Bluestone, Qizhi Tang
Keywords CAR, CAR T cell, CD28, chimeric antigen receptor, dimer, heterodimerization, hinge domain, transmembrane domain
Abstract

Anti-CD19 chimeric antigen receptor (CD19-CAR)-engineered T cells are approved therapeutics for malignancies. The impact of the hinge domain (HD) and the transmembrane domain (TMD) between the extracellular antigen-targeting CARs and the intracellular signaling modalities of CARs has not been systemically studied. In this study, a series of 19-CARs differing only by their HD (CD8, CD28, or IgG) and TMD (CD8 or CD28) was generated. CARs containing a CD28-TMD, but not a CD8-TMD, formed heterodimers with the endogenous CD28 in human T cells, as shown by co-immunoprecipitation and CAR-dependent proliferation of anti-CD28 stimulation. This dimerization was dependent on polar amino acids in the CD28-TMD and was more efficient with CARs containing CD28 or CD8 HD than IgG-HD. The CD28-CAR heterodimers did not respond to CD80 and CD86 stimulation but had a significantly reduced CD28 cell-surface expression. These data unveiled a fundamental difference between CD28-TMD and CD8-TMD and indicated that CD28-TMD can modulate CAR T-cell activities by engaging endogenous partners.

Year of Publication
2021
Journal
Frontiers in immunology
Volume
12
Number of Pages
639818
Date Published
12/2021
ISSN Number
1664-3224
DOI
10.3389/fimmu.2021.639818
Alternate Journal
Front Immunol
PMID
33833759
PMCID
PMC8021955