T cell receptors (TCRs) are crucial for immune recognition. They're made of α and β chains that team up with CD3 proteins to form a complex that spots antigens and kicks off T cell activation. This setup allows T cells to recognize a vast array of potential threats.

TCR genes mix and match to create a diverse array of receptors. This genetic shuffling, along with CD4 and CD8 co-receptors, helps T cells respond to many different antigens. When a TCR finds its match, it triggers a cascade of signals that wake up the T cell and get it ready to fight.

T Cell Receptor Structure and Function

Structure of TCR and CD3 complex

• TCR structure consists of heterodimer with α and β chains (γ and δ in small subset) containing variable (V) and constant (C) regions with extracellular, transmembrane, and short cytoplasmic domains enabling antigen recognition and signal transduction
• CD3 complex composed of CD3γ, CD3δ, CD3ε, and CD3ζ chains associates with TCR for signal transduction through immunoreceptor tyrosine-based activation motifs (ITAMs) initiating intracellular signaling cascades
• TCR-CD3 complex assembly involves TCR αβ heterodimer associating with CD3 subunits in stoichiometry: TCR αβ - CD3 γε - CD3 δε - CD3 ζζ forming functional receptor complex for antigen recognition and T cell activation

TCR gene rearrangement and diversity

• TCR gene loci comprise α chain with V and J gene segments and β chain with V, D, and J gene segments providing raw genetic material for diverse receptor generation
• V(D)J recombination initiated by RAG1 and RAG2 enzymes creates DNA double-strand breaks at recombination signal sequences (RSS) repaired by non-homologous end joining (NHEJ) generating unique TCR sequences
• Diversity generation mechanisms include combinatorial diversity from multiple V, D, and J segments, junctional diversity through addition or deletion of nucleotides at junctions, and pairing of different α and β chains producing vast TCR repertoire (estimated $10^15$ - $10^18$ possible combinations)
• Allelic exclusion ensures expression of only one functional TCR per T cell maintaining antigen specificity and preventing autoimmunity

Role of CD4 and CD8 co-receptors

• CD4 co-receptor expressed on helper T cells binds to MHC class II molecules enhancing TCR signaling by recruiting Lck kinase amplifying signal strength
• CD8 co-receptor expressed on cytotoxic T cells binds to MHC class I molecules also recruiting Lck kinase to enhance signaling facilitating target cell recognition
• Co-receptor function in antigen recognition stabilizes TCR-peptide-MHC complex interaction increasing sensitivity to antigen (100-fold enhancement) and contributes to T cell lineage commitment during thymic selection

TCR signaling pathways and activation

• Early signaling events involve:

  1. Lck phosphorylation of CD3 ITAMs
  2. ZAP-70 recruitment and activation
  3. LAT phosphorylation and formation of signalosome initiating signal transduction cascade

• Downstream signaling pathways include calcium signaling activating NFAT transcription factor, MAPK cascade activating AP-1 transcription factor, and PKC-θ activation leading to NF-κB activation regulating gene expression

• Integration of signaling pathways activates multiple transcription factors inducing genes involved in T cell activation and differentiation controlling cellular responses

• T cell responses importance includes cytokine production (IL-2, IFN-γ), proliferation, and differentiation into effector and memory T cells shaping adaptive immune responses

• Co-stimulatory signals like CD28-B7 interaction provide additional activation signals preventing anergy and promoting full T cell activation ensuring proper immune response regulation