PEPTIDE ANTAGONISTS THAT PROMOTE POSITIVE SELECTION ARE INEFFICIENT AT T-CELL ACTIVATION AND THYMOCYTE DELETION

We set out to determine whether thymocytes from T cell receptor (TCR) transgenic animals specific for a class I-restricted determinant from ovalbumin (OVA) showed the same fine specificity for antigen-driven de letion in single-cell suspension culture as required for mature T cell activation. The transgenic TCR is specific for the K-b-restricted pep tide OVA(257-264) (SIINFEKL) which is known to have four TCR contact r esidues at position 1, 4, 6, and 7 from the crystal structure of this fragment in complex with K-b. OVA(257-264) analogs systematically subs tituted at each of these positions were assayed for their ability to p romote immature double-positive thymocyte deletion or mature T cell ac tivation of a cytotoxic T lymphocyte line derived from this transgenic mouse. In the absence of additional antigen-presenting cells, single- cell thymocyte suspensions showed that the specificity for double-posi tive thymocyte deletion and mature T cell activation was virtually ide ntical, demonstrating a limited cross-reactivity with a number of vari ants having conservative substitutions at these exposed residues. Thes e peptides were considerably more efficient at both thymic deletion an d mature T cell activation than a number of non-conservative substitut ion analogs known to act as antagonists of OVA(257-264) and capable of selecting transgenic T cells in thymic organ culture. Therefore, both peripheral T cell activation and thymic deletion have an overall simi lar pattern of peptide specificity which differs from that required fo r positive selection. This suggests that a subset of major histocompat ibility complex-presented peptides could promote positive selection wi thout causing either thymic deletion or peripheral activation of those selected T cells.