title: Fine epitope specificity of antibodies against interleukin-2 explains their paradoxical immunomodulatory effects.
abstract: The functional dichotomy of antibodies against interleukin-2 (IL-2) is thought to depend upon recognition of different cytokine epitopes. Beyond functional studies, the only molecular evidence obtained so far located the epitopes recognized by the immunoenhancing antibodies S4B6 and JES6-5H4 within the predicted interface of IL-2 with the α receptor subunit, explaining the preferential stimulation of effector cells displaying only β and γ receptor chains. A consistent functional map of the epitope bound by the immunoregulatory antibody JES6-1A12 has now been delineated by screening the interactions of phage-displayed antigen variants (with single and multiple mutations) and antigen mimotopes. The target determinant resides in a region between the predicted interfaces with α and β/γ receptor subunits, supporting the dual inhibitory role of the antibody on both interactions. Binding by JES6-1A12 would thus convert complexed IL-2 into a very weak agonist, reinforcing the advantage of T regulatory cells (displaying the high affinity αβγ heterotrimeric receptor) to capture the cytokine by competition and expand over effector cells, ultimately resulting in the observed strong tolerogenic effect of this antibody. Detailed knowledge of the epitopes recognized by anti-IL-2 antibodies with either immunoenhancing or immunoregulatory properties completes the molecular scenario underlying their use to boost or inhibit immune responses in multiple experimental systems. The expanded functional mapping platform now available could be exploited to study other interactions involving related molecular pairs with the final goal of optimizing cytokine and anti-cytokine therapies.
authors.affiliation: Systems Biology Department; Center of Molecular Immunology; La Habana, Cuba.
authors.forename: Gertrudis
authors.initials: G
authors.lastname: Rojas
authors.affiliation: Systems Biology Department; Center of Molecular Immunology; La Habana, Cuba.
authors.forename: Yanelys
authors.initials: Y
authors.lastname: Cabrera Infante
authors.affiliation: Systems Biology Department; Center of Molecular Immunology; La Habana, Cuba.
authors.forename: Amaury
authors.initials: A
authors.lastname: Pupo
authors.affiliation: Systems Biology Department; Center of Molecular Immunology; La Habana, Cuba.
authors.forename: Tania
authors.initials: T
authors.lastname: Carmenate
keywords: cytokine; epitope mapping; immune complexes; interleukin-2 receptor; peptide library; phage display; site-directed mutagenesis