Author:
Muller Yannick D.,Nguyen Duy P.,Ferreira Leonardo M. R.,Ho Patrick,Raffin Caroline,Valencia Roxxana Valeria Beltran,Congrave-Wilson Zion,Roth Theodore L.,Eyquem Justin,Van Gool Frederic,Marson Alexander,Perez Laurent,Wells James A.,Bluestone Jeffrey A.,Tang Qizhi
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 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.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases
Subject
Immunology,Immunology and Allergy
Cited by
57 articles.
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