TCR

Each TCR is generated by V(D)J recombination using RAG1 and RAG2, producing enormous diversity from a limited genome; defects in RAG cause severe combined immunodeficiency. The receptor itself has a very short cytoplasmic tail and must signal through the associated CD3 complex, whose ITAM motifs are phosphorylated by Lck and ZAP-70 on engagement; ZAP-70 deficiency is a cause of SCID. Co-receptors determine restriction: CD4 binds MHC class II on professional antigen-presenting cells, CD8 binds MHC class I on all nucleated cells. Full activation requires two signals — TCR-peptide-MHC engagement plus B7 on the antigen-presenting cell binding CD28 — and signal one without signal two induces anergy, the basis of peripheral tolerance. CTLA-4 and PD-1 are inhibitory checkpoints exploited therapeutically by ipilimumab and nivolumab, and abatacept is a CTLA-4-Ig fusion used to blunt T-cell activation in rheumatoid arthritis. Superantigens bypass this specificity by cross-linking MHC II to the TCR V-beta region outside the peptide groove, activating vast numbers of T cells.