The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28
Autor: | 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 |
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Jazyk: | angličtina |
Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
T-Lymphocytes Lymphocyte Activation 0302 clinical medicine Receptors Immunology and Allergy Original Research Receptors Chimeric Antigen CD19 chimeric antigen receptor Chemistry CAR T cell CD28 hemic and immune systems transmembrane domain Transmembrane protein Cell biology CAR Transmembrane domain medicine.anatomical_structure Medical Microbiology 030220 oncology & carcinogenesis Dimerization Signal Transduction lcsh:Immunologic diseases. Allergy T cell Antigens CD19 Immunology chemical and pharmacologic phenomena Vaccine Related 03 medical and health sciences Protein Domains CD28 Antigens hinge domain medicine Humans Antigens CD86 heterodimerization Chimeric Antigen dimer Chimeric antigen receptor stomatognathic diseases 030104 developmental biology lcsh:RC581-607 human activities CD8 CD80 |
Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in immunology, vol. 12, pp. 639818 Frontiers in Immunology |
ISSN: | 1664-3224 |
Popis: | 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. |
Databáze: | OpenAIRE |
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