TCR Flashcards
(9 cards)
(5) TCR Overview
The T cell receptor (TCR) is a membrane-bound glycoprotein expressed on the surface of T lymphocytes, responsible for the antigen specificity of cellular immunity. It enables T cells to recognize processed antigenic peptides presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells (APCs) or infected target cells. Unlike antibodies produced by B cells, the TCR does not exist in a soluble form and has lower intrinsic binding affinity to its ligands. The discovery of the TCR came later than that of the B cell receptor, owing to the structural complexity and membrane localization of the receptor. Its structure and genetic basis were uncovered in the 1980s using a combination of immunological, biochemical, and molecular biology methods.
(5) TCR Structure
The majority of T cells express an αβ TCR, composed of one alpha and one beta chain, each containing a variable (V) and constant (C) region, followed by a transmembrane domain and a short cytoplasmic tail. These regions are structurally homologous to the Fab fragment of immunoglobulins. Each chain spans approximately 60–75 amino acids per domain and contains an intra-chain disulfide bond for stability. The variable regions form the antigen-binding site and contain three complementarity-determining regions (CDRs): CDR1 and CDR2 contact the MHC molecule, while CDR3—the most diverse—contacts the peptide in the MHC groove. An additional hypervariable region, HV4, found in the β chain, does not typically contact antigen but may interact with superantigens and is not classified as a true CDR.
(5) TCR & CD3 Complex
The TCR is non-covalently associated with the CD3 complex, a multi-subunit structure essential for surface expression and signal transduction. The CD3 complex consists of three dimers: γε, δε, and a ζζ homodimer (or less commonly ζη). These chains contain immunoreceptor tyrosine-based activation motifs (ITAMs) in their cytoplasmic tails—1 ITAM in γ, δ, and ε chains and three ITAMs in each ζ chain—which serve as docking sites for signaling molecules upon receptor engagement. The transmembrane domains of both TCR and CD3 contain charged residues that facilitate assembly via electrostatic interactions. The TCR-CD3 complex acts as a functional unit: the TCR provides ligand specificity, while CD3 transduces the activation signal into the cell.
(4) Co-receptors for TCR
TCR engagement with peptide-MHC complexes is inherently of low affinity, typically with a dissociation constant (Kd) between 10⁻⁴ and 10⁻⁷ M. This necessitates the involvement of co-receptors CD4 and CD8, which stabilize the interaction and recruit the Src family kinase Lck to the receptor complex. CD4 is a 55 kDa monomer composed of four Ig-like domains (D1–D4) and binds to the β2 and α2 domains of MHC class II, while CD8 is a heterodimer (αβ or αα) that binds the α2 and α3 domains of MHC class I. Lck, associated with the cytoplasmic tails of these co-receptors, phosphorylates the ITAMs on CD3 upon TCR engagement, initiating downstream signaling.
(5) TCR Activation Signalling Cascade
Upon ITAM phosphorylation, ZAP-70 is recruited via its SH2 domains and activated, leading to the phosphorylation of scaffold proteins such as LAT (Linker for Activation of T cells) and SLP-76. These scaffolds assemble additional signaling molecules including Itk, PLCγ1, and Grb2, activating multiple signaling pathways: IP₃-mediated calcium influx, activation of calcineurin and NFAT, DAG-mediated PKCθ activation, and MAPK cascades leading to AP-1 and NF-κB activation. These transcription factors coordinate the expression of cytokines such as IL-2, co-stimulatory molecules, and cell cycle regulators essential for T cell proliferation and effector differentiation. The immunological synapse formed at the T cell–APC interface organizes these signaling complexes into a stable structure called the SMAC (supramolecular activation cluster). Cytoskeletal proteins such as talin help anchor and stabilize the TCR–MHC interaction within this synapse.
(7) TCR Diversity/Assembly
TCR diversity is generated through a somatic gene rearrangement process known as V(D)J recombination, which occurs in developing thymocytes in the thymus. The α-chain locus on chromosome 14 comprises V and J segments, while the β-chain locus on chromosome 7 includes V, D, and J segments. This recombination process is directed by recombination signal sequences (RSSs), which consist of conserved heptamer and nonamer sequences separated by either 12 or 23 base pairs—enforcing the 12/23 rule. Recombination is mediated by the RAG1 and RAG2 recombinases, which introduce double-stranded breaks at RSSs. Additional diversity arises from imprecise joining, P-nucleotide addition, and N-nucleotide addition mediated by terminal deoxynucleotidyl transferase (TdT). This junctional diversity, especially in the CDR3 regions, is responsible for the enormous diversity of the TCR repertoire — estimated at over 1015 unique TCRs in the human population. Notably, unlike B cells, T cells do not undergo somatic hypermutation or class switching, meaning their antigen specificity remains constant once the receptor is formed.
(7) γδ T cells
Their ligands include phosphoantigens (presented by an isoform of CD277 (BTN3A1)), lipids (glycolipids andphospholipids) bound to CD1d, phospholipids bound to the protein EPCR and stress-induced molecules like MICA/MICB, often via NKG2D.In addition to αβ T cells, a subset of T cells express the γδ TCR, composed of γ and δ chains. These cells are less common in circulation but enriched in specific tissues such as the gut epithelium, skin, and reproductive tract. Unlike αβ T cells, γδ T cells recognize a range of non-peptide antigens without requiring classical MHC presentation. Their ligands include phosphoantigens, lipids bound to CD1d, and stress-induced molecules like MICA/MICB, often via NKG2D. γδ T cells can act rapidly in an innate-like manner, and their antigen recognition is not restricted by MHC, allowing them to respond to a broader range of pathogens. They also exhibit cytotoxicity via perforin and granulysin, and can secrete cytokines such as IFN-γ and IL-17. Their roles in infection, cancer, and autoimmunity are active areas of research, and their potential as antigen-presenting cells and immunotherapeutic tools is being increasingly explored.
(5) Superantigens and Aberrant T Cell Acitvation
An important feature of TCR biology is its interaction with microbial superantigens, such as staphylococcal enterotoxin A. Unlike conventional peptide antigens, which require intracellular processing and MHC-mediated presentation within the peptide-binding groove, superantigens bind as intact proteins to the outer surface of MHC class II molecules and simultaneously to specific residues in the Vβ region of the TCR. This interaction involves CDR1, CDR2, and the hypervariable region 4 (HV4)—a region not typically involved in antigen binding and not considered a true CDR. This bypass of antigen specificity results in polyclonal activation of a large proportion of T cells, triggering massive cytokine release, or “cytokine storm,” which can lead to toxic shock syndrome and other immunopathologies. The ability of superantigens to circumvent normal TCR specificity underscores their potential to cause severe immune dysregulation.
(4) Clinical Implications and Therapeutic Potential of the TCR
Defects in the TCR complex or its associated signaling components can lead to immunodeficiency syndromes, such as mutations in CD3 chains or ZAP-70, resulting in SCID-like phenotypes. Conversely, aberrant TCR activation is implicated in autoimmunity, graft rejection, and chronic inflammation. Clinically, engineered TCRs are used in TCR-T cell therapy, designed to recognize tumour antigens in the context of specific HLA alleles, offering a targeted approach to cancer immunotherapy. Understanding the structure, specificity, and signaling mechanisms of the TCR thus not only elucidates central principles of adaptive immunity but also provides avenues for therapeutic intervention.
