The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex.
Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3zeta CAR (MFEzeta) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEzeta CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEzeta CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3zeta transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.
Bridgeman
John S
JS
Cell Therapy Group, Cancer Research UK Department of Medical Oncology, Paterson Institute for Cancer Research, Manchester, UK.
Hawkins
Robert E
RE
Bagley
Steve
S
Blaylock
Morgan
M
Holland
Mark
M
Gilham
David E
DE
D000818:Animals; D015153:Blotting, Western; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D047468:Immunoprecipitation; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D002272:Carcinoembryonic Antigen; D011948:Receptors, Antigen, T-Cell