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

Abstract

Fetal thymic organ cultures of N15-transgenic RAG-2-/- H-2b mice on normal, beta-2 microglobulin (beta2M)-/- or transporter associated with antigen processing (rAP-1)-/- MHCl-deficient backgrounds were used to examine differentiation of thymocytes bearing a TCR specific for a viral peptide bound to H-2Kb. Strong agonists mediate negative selection in all mice whereas weak agonists are positively selecting in beta2MW-/- 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 beta2M4-/- 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 Kb-based selection, subtly modulated by peptides as revealed by X-ray crystallography.