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The Rate of Dissociation Between Antibody and Antigen Determines the Efficiency of Antibody-Mediated Antigen Presentation to T Cells

Pierre Guermonprez^*, Patrick England, Hugues Bedouelle and Claude Leclerc^1,*

^* Unité de Biologie des Régulations Immunitaires and Groupe d’ingénierie des protéines (Centre National de la Recherche Scientifique URA1129), Unité de Biochimie Cellulaire, Institut Pasteur, Paris, France

We analyzed the role of Ab affinity on Ab-mediated Ag uptake and presentation to T cells. Hen egg white lysozyme (HEL) was captured by bifunctional hybrid proteins (Fv-MalE) in which the variable fragment (Fv) of the anti-HEL mAb D1.3 was covalently linked to the Escherichia coli MalE protein. These complexes were targeted via two anti-MalE mAbs to an APC expressing a receptor for the Ab constant region. The combination of Fv-MalE and anti-MalE mAbs increased, specifically, HEL presentation. With this experimental system, we evaluated the impact of six different mutations, affecting the Fv-MalE complementarity determining regions, on the increase of HEL presentation by the corresponding hybrids. These mutations increase the dissociation rate constant (k_off), and, thus, the dissociation constant of the HEL/Fv-MalE interaction, up to 650-fold, as compared with the wt Fv-MalE. Increasing the k_off from 7 x 10^-4 s^-1 up to 300 x 10^-4 s^-1 did not interfere with the enhancement of HEL presentation. A mutant with a k_off of 600 x 10^-4 s^-1 had a reduced enhancement ability, and mutants with k_off higher than 5700 x 10^-4 s^-1 did not enhance HEL presentation at all. These results show that affinity determines the efficiency of Ab-mediated Ag presentation to T cells. One consequence is that affinity maturation in specific B lymphocytes can drastically enhance their ability to collaborate with T cells in an MHC-restricted way. This may contribute to the selection of high affinity B cell clones.

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