The Journal of Immunology, Vol 155, Issue 2 662-673, Copyright © 1995 by American Association of Immunologists

ARTICLES

Lack of strict correlation of functional sensitization with the apparent affinity of MHC/peptide complexes for the TCR

BK al-Ramadi, MT Jelonek, LF Boyd, DH Margulies and AL Bothwell
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.

We describe a comprehensive analysis of the effect of avidity of TCR- MHC/peptide interaction on activation of the (p2Ca). In study, monosubstituted variants of p2Ca were used and assessed for binding to purified H-2Ld, binding of H-2Ld/peptide complexes to sTCR, and ability to activate 2C cells to two independent effector functions. Among the > 20 variants analyzed, functional activity of most peptides that bound the MHC well correlated with the strength of interaction of MHC/peptide complexes with sTCR. However, with some variants, a clear discordance between the apparent TCR-MHC/peptide affinity and biologic function was observed, demonstrating that the former cannot always be gauged by the latter. In the case of L4 peptide (phenylalanine at position 4 substituted with leucine), peptide/MHC complexes showed no detectable binding to sTCR, indicating a 10-fold or greater decrease in affinity. Nevertheless, this peptide sensitized target cells for lysis at a level equivalent to the parental peptide. A clearer understanding was revealed by studying the extent to which activation by variant peptides was dependent on CD8. Our data indicate that resistance to anti-CD8 mAb blocking correlates with strong binding affinity between sTCR and MHC/peptide complexes. These data suggest that, for the activation of CTL function, the absolute level of intrinsic affinity of TCR for MHC/peptide ligand is not a single critical determinant, but rather, that activation is governed by the compound influence of several factors, which ensures a minimum threshold of intracellular triggering is reached to elicit the response.

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