Defective activation of mitogen-activated protein kinase after allogeneic bone marrow transplantation

• DOI: 10.1182/blood.v88.6.2334.bloodjournal8862334
• Publication Date: 2019-10-11T12:38:45Z
• Authors: C Pignata; JS Sanghera; RJ Soiffer; S Chartier; M Eder; SL Pelech; J Ritz
• Keywords: Adult; T-Lymphocytes; Calcium-Calmodulin-Dependent Protein Kinases; Cell Cycle; Receptors, Antigen, T-Cell; Humans; Middle Aged; Lymphocyte Activation; Phosphoproteins; Phosphotyrosine; Bone Marrow Transplantation; Signal Transduction; 3. Good health

Allogeneic bone marrow transplant (BMT) recipients have increased susceptibility to infections for prolonged periods after phenotypic reconstitution of donor cells. This immunodeficiency status is characterized by multiple T-cell functional abnormalities. This study was designed to investigate several signaling pathways involved in T- cell activation during this period of immune deficiency. In initial experiments using equal numbers of CD3+ cells or highly purified T-cell subpopulations obtained from normal controls and BMT recipients, we confirmed that abnormal T-cell proliferation after CD3 cross-linking, phytohemagglutinin stimulation, or phorbol myristate acetate (PMA) stimulation of peripheral blood mononuclear cells from BMT recipients was due to a qualitative T-cell deficiency rather than to low numbers of circulating T cells. We next investigated the ability of the T-cell receptor/CD3 complex to transduce signals via receptor-associated protein tyrosine kinases. In all BMT recipients, CD3 cross-linking induced protein tyrosine phosphorylation of several proteins in a similar fashion to that seen in controls, including phosphorylation of a 21-kD protein that represents the zeta subunit of the receptor itself. Further investigation showed that CD3 cross-linking and PMA stimulation did not increase 42–44-kD mitogen-activated protein kinase (MAPK) activity. The failure of MAPK activation in BMT recipients occurred despite tyrosine phosphorylation of the 42–44-kD proteins, which, in normal controls, parallels enzyme activation. Our results indicate that T-cell immunodeficiency in BMT recipients is associated with a selective failure of MAPK activation, possibly related to abnormal posttranslational positive regulation of this enzyme.