AGONIST PEPTIDE MODULATES T-CELL SELECTION THRESHOLDS THROUGH QUALITATIVE AND QUANTITATIVE SHIFTS IN CD8 CORECEPTOR EXPRESSION

Engagement of the TCR is a pivotal step in thymocyte development, ulti mately resulting in the survival (positive selection) or loss (negativ e selection) of developing T cells, The roles of peptides and stromal cell interactions necessary for these selection events, however, are s till poorly understood, To investigate the effects of agonist peptide in positive selection, we used a novel cell suspension model for in vi tro thymic positive selection in adults. Target thymocytes from H-2D(b )-restricted TCR transgenic mice, specific to the lymphocytic choriome ningitis virus (LCMV) peptide bred on a non-selecting MHC background ( H-2(d) or TAP-1-/-), were co-cultured with freshly isolated H-2(b) thy mic stromal cells. In the presence of selecting stroma the nominal ago nist LCMV peptide induced apoptosis at high concentrations and at low concentrations enhanced the efficiency of positive selection both in n umbers of cells 'rescued' and kinetics of appearance of selected singl e-positive cells, We further illustrate down-modulation of CD8 alpha b eta or CD8 beta at high but non-deleting concentrations of agonist pep tide, This highlights the ability of the T cell, within the window of positive selection, to modify surface co-receptors both qualitatively and quantitatively in response to increasing avidity TCR-peptide-MHC i nteractions. The direct consequence of this would be to lower the tota l signaling events below the threshold for apoptosis induction, Hence if self peptide were not presented in sufficient quantities in the thy mus, autoreactive cells may escape deletion and may actually be positi vely selected.