We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
CD3ζ-based chimeric antigen receptors mediate T cell activation via cis- and trans-signalling mechanisms: implications for optimization of receptor structure for adoptive cell therapy.
- Authors
Bridgeman, J. S.; Ladell, K.; Sheard, V. E.; Miners, K.; Hawkins, R. E.; Price, D. A.; Gilham, D. E.
- Abstract
Chimeric antigen receptors ( CARs) can mediate redirected lysis of tumour cells in a major histocompatibility complex ( MHC)-independent manner, thereby enabling autologous adoptive T cell therapy for a variety of malignant neoplasms. Currently, most CARs incorporate the T cell receptor ( TCR) CD3ζ signalling chain; however, the precise mechanisms responsible for CAR-mediated T cell activation are unclear. In this study, we used a series of immunoreceptor tyrosine-based activation motif ( ITAM)-mutant and transmembrane-modified receptors to demonstrate that CARs activate T cells both directly via the antigen-ligated signalling chain and indirectly via associated chains within the TCR complex. These observations allowed us to generate new receptors capable of eliciting polyfunctional responses in primary human T cells. This work increases our understanding of CAR function and identifies new avenues for the optimization of CAR-based therapeutic interventions.
- Subjects
CD3 antigen; CHIMERIC proteins; ANTIGEN receptors; CELLULAR therapy; MAJOR histocompatibility complex; T cell receptors; TYROSINE
- Publication
Clinical & Experimental Immunology, 2014, Vol 175, Issue 2, p258
- ISSN
0009-9104
- Publication type
Article
- DOI
10.1111/cei.12216