Defective interleukin 2 receptor expression is associated with the T cell disfunction subsequent to bone marrow transplantation

Abstract

In the present work we have used monoclonal antibodies (mAb) as probes to attempt a dissection of the mechanisms underlying the immunodeficiency subsequent to bone marrow transplantation (BMT). To this end we have studied 19 allogeneic BMT recipients, analyzing the proliferative response of peripheral blood mononuclear cells (PBMC) after activation with either phytohemagglutinin (PHA), anti-CD3 or anti-CD 2 mAb. All patients presented normal proportions of CD2+ and CD3+ lymphocytes, as assessed by flow cytometry. Our results indicated that in most cases both CD 2 and CD 3-mediated activation pathways were inefficient to trigger normal T cell proliferation. The addition of exogenous interleukin 2 (IL 2) did not restore in most cases the proliferative response, pointing out that additional defects contribute to the hyporesponsiveness. This was more evident in the group of patients studied during the first 6 months. To further dissect the T cell defect we analyzed the effect of a phorbol ester (phorbol myristate acetate, PMA), which activates protein kinase C, on the anti-CD 3-induced response. Our data showed that PMA synergized with anti-CD 3 similarly to exogenous IL 2, and restored the proliferative response only in certain cases. The expression of IL 2 receptors (CD 25) as assessed by cytofluorimetry, after either PHA or anti-CD 3 and PMA stimulation, was shown to be depressed, and the addition of IL 2 did not restore it. Finally, we observed that the early increase of intracytoplasmic Ca2+ after anti-CD 3 stimulation was comparable to that detected in normal PBMC. Altogether these results indicate that a diminished CD 25 expression is associated with the T cell defect, and cannot apparently be attributed to an inability of the CD 3 molecule to transduce early activation signals thus suggesting that either protein kinase C itself or an as yet undefined metabolic step preceding IL 2 receptor expression is abnormal in variable proportions of T cells after BMT, and constitutes another manifestation of this complex immunodeficiency.