Development of immunoregulatory therapy via CD26 activation pathway.

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CD26, a 110-KDa cell surface glycoprotein, exhibits dipeptidyl peptidase IV (DPPIV) enzyme activity and plays an important role in T cell costimulation. We previonsly demonstrated that CD26 is directly associated with adenosine deaminase (ADA) and that cells expressing ADA and CD26 on the surface were much more resistant to the inhibitory effect of adenosine, suggesting that ADA on the cell surface via CD26 appears to overcome the inhibitory effect of the elevated extracellular adenosine. However, previous studies have not yet determined whether there is a specific ADA binding domain on CD26, whether the interaction of ADA and CD26 on the cell surface has a direct immunoregulatory effecton T cell activation, and whether CD26 on the cell surface involves resistance to the inhibitory effect of adenosine.We found that the residues of Leucine_<340>, Valine_<341>, Alanine_<342>and Arginine_<343> on the CD26 molecule were essential amino acids for ADA binding. When these amino acids were mutated and transfected into Jurkat cells, the resultant CD26 transfectants expressed only CD26, not ADA,on the cell surface. The amount of IL-2 produced by wild-type and mutated CD26 transfectants was almost the same following stimulation with anti-CD3 plus PMA.However, the mutated CD26 transfectants were much more sensitive to the inhibitory effect of adenosine on IL-2 production than were the wild CD26 transfectants. These data suggest that ADA on the cell surface does not directlyinvolve T cell activation. Conversely, CD26 alone does not result in modulating the inhibitory effect of adenosine. Only the ADA bound to CD26 on the cell surface was functional and could counteract the inhibitory effect of elevated extracellular adenosine.