Disparate peptide-dependent thymic selection outcomes in beta2M-deficient mice versus TAP-1-deficient mice: implications for repertoire formation

Fetal thymic organ cultures of N15-transgenic RAG-2(-/-) H-2(b) mice on normal, beta-2 microglobulin (beta2M)(-/-) or transporter associated with antigen processing (TAP-1)(-/-) MHCI-deficient backgrounds were used to examine differentiation of thymocytes bearing a TCR specific for a viral peptide bound to H-2K(b). Strong agonists mediate negative selection in all mice whereas weak agonists are positively selecting in beta2M(-/-) mice but negatively selecting on TAP-1(-/-) or normal backgrounds. Very weak agonists and very weak antagonists are generally without effect in beta2M(-/-) mice yet foster differentiation in TAP-1(-/-) animals. The 20-40-fold reduction in beta2M(-/-) thymic H-2Kb surface expression suggests that the avidity of the TCR for peptide-MHCI accounts for these differences, consistent with effects of TCR density and individual thymic-peptide abundance in peptide-MHC complexes. TCR-self-MHC interaction dominates K-b-based selection, subtly modulated by peptides as revealed by X-ray crystallography.