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

Frontiers in immunology 2021

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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 IgG4) 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 IgG4-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. Copyright © 2021 Muller, Nguyen, Ferreira, Ho, Raffin, Valencia, Congrave-Wilson, Roth, Eyquem, Van Gool, Marson, Perez, Wells, Bluestone and Tang.

Citation

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. The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28. Frontiers in immunology. 2021;12:639818