T Cell Receptor Structure

T Cell Receptor Structure

The T cell receptor (TCR) is a heterodimeric cell surface protein complex that serves as the antigen-recognition apparatus of T lymphocytes. Unlike antibodies, which can recognize free-floating antigens, T cell receptors recognize peptide fragments presented by Major Histocompatibility Complex (MHC) molecules on the surface of other cells. This fundamental mechanism underlies all T cell-mediated immunity, from pathogen defense to tumor surveillance.

Overview

T cells are central orchestrators and effectors of adaptive immunity. Their ability to recognize specific antigens depends entirely on the T cell receptor—a molecule that must accomplish the remarkable feat of distinguishing foreign peptides from the thousands of self-peptides constantly displayed on every nucleated cell in the body.

Two Types of T Cell Receptors

T cells express one of two types of TCRs:

This article focuses primarily on the αβ TCR, which is the dominant receptor in peripheral blood and the principal target for most clinical and research applications.

Molecular Architecture

The αβ Heterodimer

Each αβ TCR consists of two transmembrane glycoprotein chains—alpha (α) and beta (β)—linked by a disulfide bond near the cell membrane. Both chains share a common architectural blueprint inherited from the immunoglobulin superfamily.

Domain Organization:

Each chain is approximately 280-300 amino acids in length, with the extracellular portion organized into two immunoglobulin-like domains—one variable and one constant.

Chain Composition and Gene Segments

Alpha Chain (TRA locus, chromosome 14):

• Variable region encoded by Vα and Jα gene segments
• No D segment (simpler rearrangement than β chain)
• ~70 functional Vα genes and 61 Jα genes in humans
• Extensive junctional diversity at V-J junction

Beta Chain (TRB locus, chromosome 7):

• Variable region encoded by Vβ, Dβ, and Jβ gene segments
• Two D-J-C clusters provide additional diversity
• ~52 functional Vβ genes, 2 Dβ genes, and 13 Jβ genes
• Greater junctional diversity due to D segment and two N-nucleotide additions

Three-Dimensional Structure

The TCR heterodimer adopts a characteristic “Y-shaped” structure:

• Membrane-distal: Variable domains form the antigen-binding site
• Membrane-proximal: Constant domains provide structural stability
• Transmembrane: Single-pass transmembrane helices with charged residues for CD3 association
• Cytoplasmic: Very short (3-5 amino acids)—insufficient for signaling, hence CD3 requirement

Complementarity-Determining Regions (CDRs)

The antigen-binding site of the TCR is formed by six loops called complementarity-determining regions (CDRs)—three from each chain. These loops create the surface that contacts the peptide-MHC complex.

CDR1 and CDR2: Framework Contact

Characteristics:

• Encoded entirely within germline V gene segments
• Sequence determined by V gene usage
• Relatively conserved within V gene families
• More predictable from sequencing data

Function:

• Primarily contact the α-helices of the MHC molecule
• Important for MHC restriction
• Contribute to the diagonal binding orientation of TCR on pMHC
• May also contact peptide termini

Structural Features:

CDR3: The Hypervariable Region

The CDR3 is the most variable region of the TCR and is central to antigen specificity:

CDR3α Formation:

[End of Vα]——junction——[Start of Jα]

CDR3β Formation:

[End of Vβ]—[N-nucleotides]—[Dβ segment]—[N-nucleotides]—[Start of Jβ]

Sources of CDR3 Diversity:

1. Combinatorial diversity: Different V, (D), J gene combinations
2. Junctional diversity: Imprecise joining at segment boundaries
3. N-nucleotide additions: Random nucleotides added by TdT enzyme at each junction
4. P-nucleotides: Palindromic sequences from hairpin opening during V(D)J recombination
5. Exonuclease trimming: Removal of germline nucleotides

CDR3 as a Molecular Fingerprint:

The CDR3 sequence serves as a unique identifier for each T cell clone:

• CDR3β is typically 10-15 amino acids (though ranges from 8 to 20+)
• CDR3α is typically 8-13 amino acids
• Together, CDR3 sequences can uniquely identify clonotypes in repertoire studies

Why CDR3β is Often Prioritized:

In many research and clinical applications, CDR3β is analyzed preferentially because:

• Contains a D segment → additional diversity
• Two N-nucleotide addition sites → more junctional diversity
• Single β-selection checkpoint ensures one TCRβ per cell (strict allelic exclusion)
• TCRα has less strict allelic exclusion and may undergo multiple rearrangements

Antigen Recognition: The Trimolecular Complex

TCR recognition is inherently a trimolecular interaction involving:

1. TCR (on T cell surface)
2. Peptide antigen (8-25 amino acids, depending on MHC class)
3. MHC molecule (on antigen-presenting cell or target cell)

Binding Geometry

The TCR binds diagonally across the peptide-MHC complex:

• Vα typically positioned over the peptide N-terminus and MHC α2 helix (Class I) or β1 helix (Class II)
• Vβ typically positioned over the peptide C-terminus and MHC α1 helix
• CDR3 loops make the most direct peptide contacts
• CDR1/CDR2 loops primarily contact MHC helices

This diagonal orientation is remarkably conserved across most characterized TCR-pMHC structures, suggesting evolutionary optimization.

Peptide Contact

The TCR “reads” only a portion of the presented peptide:

• Central residues (typically positions 4-6 for Class I, positions 2-5 for Class II) are most contacted
• Terminal residues may be buried in MHC pockets
• A few key peptide residues often dominate the interaction

Binding Affinity

TCR-pMHC interactions are notably weaker than antibody-antigen interactions:

This weak, short-lived binding has important functional consequences:

• Enables serial triggering (one pMHC can activate multiple TCRs sequentially)
• Allows T cell scanning of many pMHC complexes
• Requires coreceptor (CD4/CD8) engagement for stable interaction
• Necessitates signal amplification through CD3 complex

MHC Restriction

T cells exhibit MHC restriction—they only recognize peptide antigens presented by specific MHC alleles. This restriction is established during thymic selection and determines which MHC class a T cell can respond to.

Class I Restriction (CD8+ T Cells)

Class II Restriction (CD4+ T Cells)

Coreceptor Function

CD4 and CD8 coreceptors stabilize TCR-pMHC interactions:

• CD8 (αβ heterodimer or αα homodimer): Binds invariant region of MHC Class I α3 domain
• CD4 (single chain): Binds invariant region of MHC Class II β2 domain
• Both recruit Lck kinase to the TCR complex, initiating signaling

The CD3 Complex

The TCR heterodimer lacks intrinsic signaling capacity—its cytoplasmic tails are too short. Signal transduction requires association with the CD3 complex.

CD3 Components

ITAM: Immunoreceptor Tyrosine-based Activation Motif—the signaling sequences phosphorylated upon TCR engagement.

Complete TCR-CD3 Complex

The stoichiometry of the complete complex is:

TCRαβ : CD3γε : CD3δε : CD3ζζ (1:1:1:1)

This 8-chain complex is required for:

• Surface expression of the TCR
• Signal transduction upon antigen recognition
• Full T cell activation

TCR Gene Nomenclature

The IMGT (ImMunoGeneTics) database provides standardized nomenclature for TCR genes:

Alpha Chain (TRA)

Beta Chain (TRB)

Nomenclature Examples

A complete clonotype description includes:

TRAV21*01 / TRAJ48*01 (CDR3α: CAVRDPNYGQNFVF)
TRBV7-2*01 / TRBD2*01 / TRBJ2-7*01 (CDR3β: CASSLGQAYEQYF)

Clinical Relevance

Disease-Specific TCR Signatures

Certain diseases are associated with T cell clones bearing characteristic TCR features:

Importance of Paired Chain Analysis

Single-chain sequencing (typically β-chain only) can:

• Identify clonal expansions
• Track known clonotypes
• Provide repertoire diversity metrics

Paired chain sequencing is required to:

• Definitively establish antigen specificity
• Distinguish disease-associated from bystander clones
• Enable functional validation through TCR cloning
• Confirm TCR-peptide-MHC interactions

Therapeutic Applications

• TCR-engineered T cells: Patient T cells modified to express specific TCRs for cancer immunotherapy
• TCR-based diagnostics: Identifying T cell signatures for disease detection
• Vaccine development: Characterizing protective T cell responses

Key Concepts

1. αβ TCR is a heterodimer of alpha and beta chains, each with variable and constant regions

2. CDR3 is the most variable region and primarily determines antigen specificity; formed at V-(D)-J junctions with extensive junctional diversity

3. MHC restriction means TCRs only recognize peptide antigens presented by specific MHC molecules—established during thymic development

4. TCR-pMHC binding is relatively weak (μM affinity), enabling serial triggering and rapid scanning

5. The CD3 complex provides the signaling capability that the TCR itself lacks

6. Paired chain analysis is essential for definitive antigen specificity determination and clinical applications

Related Articles

• V(D)J Recombination — How TCR diversity is generated through somatic recombination
• T Cell Development — Thymic selection and MHC restriction establishment
• HLA System — The human MHC genes and antigen presentation
• Antigen Presentation — How peptides are loaded onto MHC molecules
• Immune Repertoire — Population-level TCR diversity

References

1. Rossjohn J, et al. (2015). T cell antigen receptor recognition of antigen-presenting molecules. Annual Review of Immunology, 33:169-200.

2. La Gruta NL, et al. (2018). Understanding the drivers of MHC restriction of T cell receptors. Nature Reviews Immunology, 18:467-478.

3. Glanville J, et al. (2017). Identifying specificity groups in the T cell receptor repertoire. Nature, 547:94-98.

4. Garcia KC, et al. (2009). The molecular basis of TCR germline bias for MHC is surprisingly simple. Nature Immunology, 10:143-147.