A T-Cell Receptor Breaks the Rules
Yang et al. genetically engineered genes for a nonclassically functioning TCR into the T cells of a patient, and when this was done, the recipient’s T cells acquired similar cancer-killing capabilities.
Most mature T cells function immunologically when a T-cell receptor (TCR) located on the cell surface encounters and engages its ligand, a major histocompatability complex (MHC), which displays a specific part of a target protein called an antigen. This antigen-presenting complex is assembled from one of the dozen or so MHC molecules that every person inherits from their parents; and the antigen fragment, called a peptide epitope, is excised from one of thousands of possible proteins—originally part of an invading pathogen or a cancer cell—that T cells are capable of identifying and attacking. The framework of an MHC molecule holding a centrally displayed or “presented” peptide is what engages the TCR and triggers T-cell action. This role of MHC molecules presenting antigens to the TCR is a central tenet of immunology, with the fit between a TCR and the MHC framework actually “hardwired” into their three-dimensional structures.
Dr. Ken-ichi Hanada, M.D., Ph.D., and James Yang, M.D., and their colleagues, working in CCR’s Surgery Branch have recently discovered a new ligand that also can trigger T-cell action through its TCR, but without involving the classical participation of any MHC molecule. During an analysis of T-cell responses against human renal cell carcinoma (RCC), they identified a CD4+ T-cell line bearing a TCR that was immunologically activated by nearly all human renal cancer cells, regardless of the array of MHC molecules involved in the framework. Though immune engagement of this TCR was not classical, it still resulted in the destruction of renal cancer cells, growth of the T-cell population, and the release of cytokines (immune response signaling molecules). Of importance was the fact that it was possible to genetically engineer genes for this variant TCR into the T cells of a patient, and when this was done, the recipient’s T cells acquired similar nonclassical cancer-killing capabilities.
By dissecting the underlying mechanism of this new ligand’s ability to non-classically stimulate an immune response, Yang and colleagues discovered that the actual stimulating structure was the protein TNF-related apoptosis inducing ligand (TRAIL), bound to one of its normal receptors called death receptor 4 (DR4) on the renal carcinoma cells. Furthermore, in a complex two-way interaction, matrix metalloproteinase 14 expressed on RCC cells was responsible for liberating TRAIL bound to the T-cell surface so that it could then bind to DR4 on the renal cancer target. This complex was then recognized directly by the TCR through a complementarity-determining region called 3α (CDR3α). To validate that this was indeed the ligand that was interacting directly with the TCR, Yang and his team immobilized a recombinant TRAIL/DR4 complex on plastic and was again able to demonstrate its specific interaction with the TCR. To further prove that this newly discovered ligand was directly activating the T-cell receptor via the CDR3α site, the team made amino acid substitutions in the CDR3α of the TCR, and these changes either obliterated or enhanced target-specific recognition, depending upon what substitution was made.
This discovery of a non-MHC-linked complex that can be recognized by naturally occurring T-cell receptors broadens the concept of an immune response and may have clinical relevance for treating renal cell carcinoma, so a clinical protocol is under way to treat advanced renal cancer patients with their own T-cells that have been engineered to express a nonclassical T-cell receptor.Summary Posted: Tue, 03/01/2011
>Hanada K, Wang QJ, Inozume T, and Yang JC: Molecular identification of an MHC-independent ligand recognized by a human alpha/beta T-cell receptor. Blood. PubMed Link