POSITIVE SELECTION OF LOW RESPONSIVE, POTENTIALLY AUTOREACTIVE T-CELLS INDUCED BY HIGH AVIDITY, NON-DELETING INTERACTIONS

Using a novel cell suspension model we investigated the relative abili ties of nominal peptide and variants thereof to modulate de novo posit ive selection of lymphocytic choriomeningitis virus (LCMV)-specific TC R transgenic T cells. Confirming our earlier findings intermediate con centrations (10(-7) to 10(-5) M) of the nominal agonist peptide, p33, induced CD8 co-receptor down-modulation at the level of the entire rec eptor and the CD8 beta chain as a consequence of high but non-deleting signal interactions. Agonist peptide variants caused down-modulation of the CD8 beta chain but to a lesser degree. An antagonist peptide ca pable of inducing positive selection did not cause such modifications of the co-receptor, The positively selected TCR(hi)CD8 alpha alpha and TCR(hi)CD8(-) cells were functional but not as efficient as TCR(hi)CD 8 alpha beta cells, presumably due to lower avidity interactions in th e absence of the CD8 beta chain or entire co-receptor, CD8 beta mRNA w as absent in these cells and was not up-regulated when further stimula ted with fresh antigen-presenting cells pulsed with 10(-5) M p33 Effec tively our data suggest that it is not the agonist or antagonist natur e of a peptide per se but the overall strength of signalling that dete rmines whether a cell will be positively or negatively selected, or di e by neglect. Furthermore the agonist/antagonist properties of peptide s defined at the level of mature T cell function do not unequivocally predict their effect on positive/negative selection. The ability of th e 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 autoreac tive cells may escape into the periphery.