T Cell Receptor Structure and Function

T Cell Receptor Structure

• TCRs are composed of two chains, α and β, each containing a variable (V) and a constant (C) domain.
• V domains contain four complementarity determining regions (CDRs) involved in peptide-MHC (pMHC) recognition: CDR1, CDR2, CDR3, and HV4.
• HV4 is variable but doesn't directly contact the peptide within the pMHC complex.
• TCRγ and δ chains also contain CDR1, CDR2, CDR3, and HV4 regions.

TCR-CD3 Complex

• The cytoplasmic tails of TCR chains are too short for signal transduction.
• CD3 dimers, analogous to Igα and Igβ chains in B cells, are responsible for signaling through TCR after antigen interaction.
• The CD3 complex comprises three heterodimeric proteins with variable combinations of five ITAM-containing invariant polypeptide chains (epsilon, delta, zeta, eta, and gamma).

CD3 Complex Functions

• Signal transduction: Upon TCR engagement by pMHC, tyrosine residues in the CD3 ITAMs are phosphorylated by Lck, triggering a signaling cascade.
• Surface expression of TCR: CD3 complex associates with TCR in the endoplasmic reticulum (ER) and facilitates its transport to the T cell surface.

CD4 and CD8 Coreceptors

• CD4 and CD8 are coreceptors that bind to conserved regions of MHC class II and class I molecules, respectively.
• Binding is independent of the antigenic peptide recognized by the TCR.
• CD4+ T cells are primarily helper T cells (Th cells), while CD8+ T cells are mostly cytotoxic T cells (CTLs).
• CD4 and CD8 have two main functions:
  • Stabilize TCR-pMHC binding.
  • Recruit Lck to the TCR-CD3 complex, enhancing TCR-pMHC binding and initiating signal transduction.

TCR Gene Organization

• TCRα, β, γ, and δ polypeptide chains are encoded by TCRA, TCRB, TCRG, and TCRD loci, respectively.
• In both mouse and human, TCRA and TCRD loci are located on chromosome 14, with TCRD nested within TCRA.

T Cell Development in the Thymus

• Similar to immunoglobulin, each TCR chain has a variable (V) and a constant (C) domain.
• TCR V exon is assembled by V(D)J recombination of V, D, and J gene segments in TCRB and TCRD loci.
• The thymus plays a crucial role in selecting for self-MHC-restricted and non-self-reactive T cells (tolerant to self).
• Mature CD4+ and CD8+ T cells, exhibiting class II and class I MHC restriction, respectively, exit the thymus.

Positive Selection

• Occurs in the cortex of the thymus.
• T cells recognizing self-MHC with low or intermediate affinity receive a survival signal from cortical thymic epithelial cells (cTECs).
• Ensures self-MHC restriction.
• Cells failing positive selection undergo apoptosis.

Negative Selection

• Occurs in the medulla of the thymus.
• Also known as central tolerance.
• AIRE+ medullary thymic epithelial cells (mTECs), thymic dendritic cells, and macrophages present self-antigen presented by self-MHC.
• T cells with high affinity for self-MHC or self-antigen are eliminated.
• Ensures self-tolerance.

Activation of Th Effector Cells

• Effector Th cells are activated similarly to naïve T cells but with specific differences.
• Effector Th cells express higher levels of adhesion molecules, facilitating rapid TCR triggering.
• Activation requires significantly lower quantities of antigen/pMHC.
• Less costimulation by APC is required compared to naïve T cells.

Differential Costimulatory Requirements for Th Effector Cells

• While CD28-B7 is the major costimulatory mechanism for naïve T cell activation, effector T cells require only low levels of CD28-B7 costimulation.
• Two additional costimulatory pairs play a role:
  • OX40-OX40L: Important in Th1 responses.
  • ICOS-ICOSL: Up regulated on Th2 and Th17 cells after activation.

Superantigens

• Bypass normal immune recognition by non-specifically ligating TCR and MHC simultaneously.
• Bind to the Vβ domain of TCR and the α chain of MHC class II.
• Induce T-cell activation and proliferation, but not without costimulation.
• Two types:
  • Endogenous superantigens: Cell-membrane proteins encoded by certain viruses, e.g., Mls determinants from mouse mammary tumor virus (MTV).
  • Exogenous superantigens: Soluble proteins secreted by bacteria, e.g., exotoxins secreted by Gram-positive bacteria like staphylococcal enterotoxins, toxic-shock syndrome toxin (TSST1), and streptococcal pyrogenic exotoxins.
• T cell activation by superantigens is polyclonal and leads to overproduction of Th-cell cytokines, resulting in systemic toxicity.

Th1 Effector Functions

• Provide help to Tc and B cells.
• Offer cell-mediated and humoral defense against intracellular pathogens.
• Play a role in delayed-type hypersensitivity (DTH), including allergies.
• Secrete cytokines dominated by IL-2, IFN-γ, and lymphotoxin (LT).
  • IL-2 drives T and B cell proliferation and enhances reactive oxygen species (ROS) production by macrophages.
  • IFN-γ and LT activate macrophages, increase phagocytosis, and upregulate nitric oxide (NO) production.

Explore the intricate structure of T Cell Receptors (TCRs) and their associated CD3 complex. This quiz will cover the roles of the various domains and the signaling functions that TCRs perform upon interaction with peptide-MHC complexes. Test your understanding of how TCRs contribute to immune response.