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Original Article

Eva Richard^a, Francisco X. Arredondo-Vega^a, Ines Santisteban^a, Susan J. Kelly^a, Dhavalkumar D. Patel^a,b, and Michael S. Hershfield^a,c

^a Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710
^b Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710
^c Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710
Duke University Medical Center, Box 3049, Durham, NC 27710.919-684-4168919-684-4184

Human, but not murine, adenosine deaminase (ADA) forms a complex with the cell membrane protein CD26/dipeptidyl peptidase IV. CD26-bound ADA has been postulated to regulate extracellular adenosine levels and to modulate the costimulatory function of CD26 on T lymphocytes. Absence of ADA–CD26 binding has been implicated in causing severe combined immunodeficiency due to ADA deficiency. Using human–mouse ADA hybrids and ADA point mutants, we have localized the amino acids critical for CD26 binding to the helical segment 126–143. Arg142 in human ADA and Gln142 in mouse ADA largely determine the capacity to bind CD26. Recombinant human ADA bearing the R142Q mutation had normal catalytic activity per molecule, but markedly impaired binding to a CD26⁺ ADA-deficient human T cell line. Reduced CD26 binding was also found with ADA from red cells and T cells of a healthy individual whose only expressed ADA has the R142Q mutation. Conversely, ADA with the E217K active site mutation, the only ADA expressed by a severely immunodeficient patient, showed normal CD26 binding. These findings argue that ADA binding to CD26 is not essential for immune function in humans.

Key Words: adenosine deaminase deficiency • severe combined immunodeficiency • T lymphocyte • protein–protein interaction • adenosine deaminase complexing protein

© 2000 The Rockefeller University Press

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