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
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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