Peptide antagonists that promote positive selection are inefficient at T cell activation and thymocyte deletion

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Abstract
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 deletion in single‐cell suspension culture as required for mature T cell activation. The transgenic TCR is specific for the Kb‐restricted peptide OVA257‐264 (SIINFEKL) which is known to have four TCR contact residues at position 1, 4, 6, and 7 from the crystal structure of this fragment in complex with Kb. OVA257‐264 analogs systematically substituted at each of these positions were assayed for their ability to promote immature double‐positive thymocyte deletion or mature T cell activation 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‐positive thymocyte deletion and mature T cell activation was virtually identical, demonstrating a limited cross‐reactivity with a number of variants having conservative substitutions at these exposed residues. These peptides were considerably more efficient at both thymic deletion and mature T cell activation than a number of non‐conservative substitution analogs known to act as antagonists of OVA257‐264 and capable of selecting transgenic T cells in thymic organ culture. Therefore, both peripheral T cell activation and thymic deletion have an overall similar pattern of peptide specificity which differs from that required for positive selection. This suggests that a subset of major histocompatibility complex‐presented peptides could promote positive selection without causing either thymic deletion or peripheral activation of those selected T cells.

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