αβTCRs Differ in the Degree of Their Specificity for the Positively Selecting MHC/Peptide Ligand

Abstract

We have tested the peptide specificity of positive selection using three transgenic αβTCRs, originally selected on class II MHC (Ab) covalently bound with one peptide Eα (52–68) (Ep). The transgenic TCR specific for the cytochrome c-derived (43–58) peptide was selected on Ab bound with different arrays of endogenous peptides or the analogue of Ep covalently bound to Ab, but not on the original AbEp complex. In contrast, transgenic TCRs specific for two different analogues of the Ep peptide and Ab did not mature as CD4+ T cells in various thymic environments, including the AbEpIi− mice. These results show that TCRs can be promiscuous or specific for the selecting MHC/peptide complex, and suggest that in mice described in this study transgenic expression of the TCR changes the original requirements for the positively selecting MHC/peptide complex. Future studies will determine whether the latter phenomenon is general or specific for this system.

The effects of thymic selection on the range of T cell cross‐reactivity

“…For each of 1000 randomly generated foreign peptides presented by MHC, an average of 231 AE 15 (mean AE standard deviation) pre-selection T cell clones out of 2.5 Â 10 8 could respond to it, i.e. approximately 1 in 10 6 . Of these, 23 AE 5.5 (about 10%) survived thymic selection, with 40 AE 14 (17%) eliminated during positive selection and 168 AE 19 (73%) by negative selection.…”

“…It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].…”

“…It has been estimated that a T cell can detect an average of 10 6 different peptides [5]. However, not all T cells are equally cross-reactive; it has been observed that the number of peptides to which a single T cell can respond varies widely [6].T cell recognition of antigen is determined by binding interactions of T cell receptors (TCR) with peptide-MHC complexes (pMHC). Each T cell expresses thousands of copies of identical TCR that bind with high affinity to their cognate peptide presented by MHC.…”

“…Because a T cell's affinity for MHC depends on its affinity for self peptides, its cross-reactivity is also determined by its affinity for self peptides. In [6], there is tantalizing evidence to support this idea. In that study, Figure 3.…”

Reduction of T Cell Receptor Diversity in NOD Mice Prevents Development of Type 1 Diabetes but Not Sjögren’s Syndrome

“…The TCRβ transgenic chain originated from I-A b restricted TCR specific to Ep63 K peptide an analog of Eα 52–68 peptide in which the residue at position 63(I) was substituted with lysine [40]. To further reduce diversity of TCRs we used TCRα mini transgenic construct, used previously to create TCR mini mouse on B6 background (B6 mini ) [36].…”