T-Cell Receptor (TCR) Subunits
Overview of T-Cell Receptor (TCR)
The TCR is a disulfide-linked membrane-bound heterodimeric protein that is found on the surface of T cells and responsible for recognizing peptide antigens displayed by MHC molecules. Most TCRs usually consist of highly variable α and β chains or subunits expressed as part of a complex with the invariant CD3 chain molecules. T cells expressing these two chains are referred to as αβ T cells. Besides, a small number of T cells express variable γ and σ chains or subunits, called γσ T cells. The γδ TCR is comprised of variable γ and δ chains expressed with CD3 on a smaller subset of T cells that recognize different types of antigens. Both of these types of receptors are expressed with a disulfide-linked homodimer of ξ chains.
In the predominant αβ TCR, each of the two disulfide-linked transmembrane α and β polypeptide chains contains one N-terminal Ig-like variable (V) domain, one Ig-like constant (C) domain, a hydrophobic transmembrane region, and a short cytoplasmic region (Fig.1). The V and C regions are homologous to immunoglobulin V and C regions. In the V region of each TCR chain, there are three hypervariable, or complementarity-determining regions (CDRs), named CDR1, CDR2, and CDR3, respectively. As in antibodies, CDR3 is the most variable among different TCRs.
Figure 1. Structure of the TCR. (Abbas, 2012)
Antigen Recognition by the TCR
TCR initiates the cellular immune response by recognizing foreign peptide-MHC molecular complexes on the surface of antigen-presenting cells. Both the α and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides (Fig.2). Each TCR only recognizes as few as one to three residues of the MHC-associated peptide. TCR can recognize the antigen, but it cannot transmit signals to T cells on its own. Therefore, TCR recognition requires other protein complexes, called CD3 and ζ proteins, which together with TCR form the TCR complex. The CD3 and ζ chains transmit some of the signals that are initiated when the TCR recognizes an antigen. Additionally, T cell activation requires the participation of the co-receptor molecule, CD4 or CD8, which recognizes the non-polymorphic portion of the MHC molecule and is also involved in signal transduction.
Figure 2. Recognition of peptide-MHC complex by a TCR. (Abbas, 2012)
TCR Related Technology
Soluble TCR
Soluble TCR therapy represents a potential alternative to cell-based immunotherapies. Bispecific T cell engaging TCR can recognize tumor peptides on the cell surface. This engagement can be used to target therapeutics to this cell or engage further T cell responses.
Antibody-Coupled TCR
Antibody-coupled TCR consists of an extracellular domain, a transmembrane domain, a co-stimulatory signaling domain, and a TCR signaling domain. T cells containing antibody-coupled TCR can be used in combination with a variety of tumor-targeting antibodies to recognize different antigens and kill different types of tumors. When tumor-targeting antibodies bind to the surface of tumor cells, T cells containing antibody-coupled TCR can indirectly recognize tumor cells through the antibody's Fc domain, which enables the antibody-dependent cellular cytotoxicity (ADCC) for tumor cell killing.
TCR Modified T Cell Development
Over the years, T cells with genetically engineered TCR have proven to be a viable and potential therapeutic tool for the treatment of cancer. Therefore, the clinical development of TCR engineered T cells is critical, such as the identification and selection of TCR biomarker, TCR generation and optimization, TCR design and construction, TCR gene packaging, TCR gene delivery, TCR in vitro assay and TCR analysis, etc.
Reference
- Abbas, A. K.; Lichtman, A. H. (2012). Basic immunology: functions and disorders of the immune system. American Journal of Epidemiology. 155(2):185-186.
