The present report describes functional characteristics of a monoclonal antibody (mAb), TA/211, which is reactive with a common determinant of the human CD45 molecules. When added to purified testing human T cells, TA/211, which is itself not mitogenic, leads to a strong proliferative response in combination with submitogenic concentrations of anti-T11(2) plus anti-T11(3) mAb. Interestingly, while amplifying anti-CD2-mediated immune responses, T cell activation induced through triggering of the CD3 molecule is not enhanced by TA/211, indicating that the triggering signal provided through CD45 is restricted to alternative pathway activation. Employing T cell subsets negatively selected for the expression of CD45R molecules defined by the mAb anti-2H4 or UCHL1, respectively, it is demonstrated that resting T cells expressing the 2H4 molecules proliferate much stronger to TA/211 than the UCHL1+ T cell subset. Together with the finding that the 2H4+ T cell subset can be activated by the concomitant binding of anti-CD2 antibodies plus anti-2H4, these data strongly suggest that the high molecular weight species of CD45 expressed by unprimed T cells are themselves involved in T cell activation via the alternative pathway.