CD3-TCR Complex and Accessory Molecules

CD3-TCR Complex and Accessory Molecules

• The interaction between MHC-bound antigen and TCR is critical for both humoral and cell-mediated responses.
• A complex is formed by the three-pronged interaction of MHC-bound antigen and TCR, a complex which varies between Class I and Class II.
• MHC cell-to-cell stabilization and activation are central outputs.
• A single TCR's recognition of an antigen-MHC complex is mediated by the TCR-CD3 complex.
• Accessory molecules play an important role in cell-to-cell interaction and signal transduction.
• The initial interaction between the αβ TCR and MHC Class II is unstable, and the CD4 molecule from the T cell stabilizes the TCR-antigen-MHC complex.
• CD3 anchors the TCR and mediates antigen-MHC recognition.
• CD2 on the T cell stabilizes cell-to-cell interaction as a ligand to LFA-3 and is important for signal transduction.
• The CD3-TCR complex includes the TCR (α and β chains, or γ and δ chains in γδ T cells) and the CD3 complex (CD3γ, CD3δ, CD3ε, and CD3ζ subunits).
• The CD3 complex contains immunoreceptor tyrosine-based activation motifs (ITAMs, are phosphorylated upon TCR engagement, initiating downstream signaling events.
• ICAM-1 (on APCs) binds to LFA-1 (on T cells), promoting adhesion between T cells and APCs, facilitating the formation of an immunological synapse.
• LFA-3 (on APCs) interacts with CD2 (on T cells), contributing to the adhesion of the immunological synapse and enhancing TCR signaling.
• CD80/86 (on APCs) interacts with CD28 (on T cells), providing co-stimulatory signals that enhance TCR signaling and prevent anergy or tolerance.
• TCR engagement triggers ITAM phosphorylation in the CD3 complex, enhanced by co-stimulatory signals and downstream signaling pathways activate protein kinases and mobilize calcium ions.
• The process leads to transcription factor activation, changes in gene expression, and T cell effector functions.

Outcomes of TCR and Signal Transduction Failure

• T cell anergy is a state of functional inactivation when T cells receive insufficient co-stimulatory signals during antigen recognition.
• Anergy prevents T cell activation even when the TCR engages with an antigen, preventing inappropriate immune responses and autoimmunity.
• Lack of proper co-stimulation or signaling can lead to peripheral tolerance induction.
• Tolerance mechanisms prevent self-reactive T cell activation, avoiding autoimmune reactions.

MHC Polymorphism and Haplotypes

• Haplotypes are alternative forms of a gene at each MHC locus within the population.
• MHC loci genes are in close proximity, reducing the chance of genetic crossover.
• Most individuals inherit two sets of alleles or haplotypes from each parent.
• The human HLA complex is highly polymorphic, with multiple alleles of each Class I and Class II gene.
• Crossover contributes to diversity of the loci in the population.

MHC Haplotype Inheritance

• Studies using skin graft rejection contributed to understanding the polymorphic identity of the MHC complex in humans
• When two inbred mice with different MHC haplotypes are bred, the F1 generation inherits haplotypes from both parental strains and expresses both parental alleles, continuing the f1 progeny is histocompatible with both parental strains, meaning that progeny can accept grafts from either parent.
• Neither parent strain can accept the graft from the progeny, because Both of the MHC molecules would be foreign to the parent.
• The progeny can donate to another syngenic or identical at all genetic loci, individuals, conversely, congenital or genetically identical, except at a single genetic region, skin graft can be rejected.

T Lymphocyte Antigen Recognition

• T lymphocytes cannot directly recognize antigens on microbes/pathogens or those that have extracellular circulation.
• T cells recognize antigens presented by antigen-presenting cells like B lymphocytes, macrophages, dendritic cells, or other nucleated cells.
• T cells require peptides derived from antigens to be presented with major histocompatibility complex (MHC) molecules.
• T cells have a T cell receptor (TCR) made of an alpha-beta polypeptide chain, which recognizes peptides displayed by the MHC molecule.
• CD4 and CD8 molecules are co-receptors on CD4+ and CD8+ T cells, respectively, that bind to the MHC molecule during antigen recognition and are necessary for T cell activation.
• CD3 complex polypeptides help transduce signals for T cell activation.
• CD28 is a co-receptor that binds to the B7 molecule on nucleated or antigen-presenting cells.
• MHC molecules are proteins encoded by MHC genes located on the short arm of chromosome six.
• MHC molecules are classified into three types: MHC I, II, and III, with types I and II being important for antigen recognition by T cells.