Positive selection of low responsive, potentially autoreactive T cells induced by high avidity, non-deleting...

Using a novel cell suspension model we investigated the relative abilities of nominal peptide and variants thereof to modulate de novo positive selection of lymphocytic choriomeningitis virus (LCMV)-specific TCR transgenic T cells. Confirming our earlier findings intermediate concentrations (10(-7) to 10(-5) M) of the nominal agonist peptide, p33, induced CD8 co-receptor down-modulation at the level of the entire receptor and the CD8beta chain as a consequence of high but non-deleting signal interactions. Agonist peptide variants caused down-modulation of the CD8beta chain but to a lesser degree. An antagonist peptide capable of inducing positive selection did not cause such modifications of the co-receptor. The positively selected TCRhiCD8alpha alpha and TCRhiCD8- cells were functional but not as efficient as TCRhiCD8alphabeta cells, presumably due to lower avidity interactions in the absence of the CD8beta chain or entire co-receptor. CD8beta mRNA was absent in these cells and was not up-regulated when further stimulated with fresh antigen-presenting cells pulsed with 10(-5) M p33. Effectively our data suggest that it is not the agonist or antagonist nature of a peptide per se but the overall strength of signalling that determines whether a cell will be positively or negatively selected, or die by neglect. Furthermore the agonist/antagonist properties of peptides defined at the level of mature T cell function do not unequivocally predict their effect on positive/negative selection. The ability of the T cell to down-modulate its CD8 co-receptor in response to high but non-deleting peptide interactions during positive selection allows the survival of T cells with a broader range of affinities and represents a possible mechanism by which low responsive but potentially autoreactive cells may escape into the periphery.