Frontiers in Immunology (Mar 2021)
The CD28-Transmembrane Domain Mediates Chimeric Antigen Receptor Heterodimerization With CD28
- Yannick D. Muller,
- Yannick D. Muller,
- Yannick D. Muller,
- Duy P. Nguyen,
- Leonardo M. R. Ferreira,
- Leonardo M. R. Ferreira,
- Leonardo M. R. Ferreira,
- Patrick Ho,
- Patrick Ho,
- Patrick Ho,
- Caroline Raffin,
- Caroline Raffin,
- Roxxana Valeria Beltran Valencia,
- Zion Congrave-Wilson,
- Theodore L. Roth,
- Theodore L. Roth,
- Justin Eyquem,
- Frederic Van Gool,
- Frederic Van Gool,
- Alexander Marson,
- Alexander Marson,
- Alexander Marson,
- Laurent Perez,
- James A. Wells,
- James A. Wells,
- Jeffrey A. Bluestone,
- Jeffrey A. Bluestone,
- Qizhi Tang,
- Qizhi Tang
Affiliations
- Yannick D. Muller
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Yannick D. Muller
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Yannick D. Muller
- Department of Medicine, Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- Duy P. Nguyen
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States
- Leonardo M. R. Ferreira
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Leonardo M. R. Ferreira
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Leonardo M. R. Ferreira
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Patrick Ho
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Patrick Ho
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Patrick Ho
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Caroline Raffin
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Caroline Raffin
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Roxxana Valeria Beltran Valencia
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Zion Congrave-Wilson
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Theodore L. Roth
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Theodore L. Roth
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Justin Eyquem
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Frederic Van Gool
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Frederic Van Gool
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Alexander Marson
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Alexander Marson
- Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
- Alexander Marson
- Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes, San Francisco, CA, United States
- Laurent Perez
- Department of Medicine, Service Immunologie et Allergie, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
- James A. Wells
- Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA, United States
- James A. Wells
- Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, United States
- Jeffrey A. Bluestone
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- Jeffrey A. Bluestone
- Sean N. Parker Autoimmune Research Laboratory, University of California, San Francisco, San Francisco, CA, United States
- Qizhi Tang
- Department of Surgery, University of California, San Francisco, San Francisco, CA, United States
- Qizhi Tang
- Diabetes Center, University of California, San Francisco, San Francisco, CA, United States
- DOI
- https://doi.org/10.3389/fimmu.2021.639818
- Journal volume & issue
-
Vol. 12
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.
Keywords
