International Immunology, Vol 10, 999-1008, Copyright © 1998 by Oxford University Press
AP Chidgey and RL Boyd
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.
ARTICLES
Positive selection of low responsive, potentially autoreactive T cells induced by high avidity, non-deleting interactions
Department of Pathology and Immunology, Monash Medical School, Prahran, Australia.
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