The binding site of human adenosine deaminase for CD26/dipeptidyl peptidase IV: The Arg142Gln mutation impairs binding to CD26 but does not cause immune deficiency

Human, but not murine, adenosine deaminase (ADA) forms a complex with the c ell membrane protein CD26/dipeptidyl peptidase IV. CD26-bound ADA has been postulated to regulate extracellular adenosine levels and to modulate the c ostimulatory 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 l ocalized the amino acids critical for CD26 binding to the helical segment 1 26-143. Arg142 in human ADA and Gln142 in mouse ADA largely determine the c apacity 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 foun d with ADA from red cells and T cells of a healthy individual whose only ex pressed ADA has the R142Q mutation. Conversely, ADA with the E217K active s ite 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.