title: Defective activation of mitogen-activated protein kinase after allogeneic bone marrow transplantation.
abstract: 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.
authors.affiliation: Dana Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Pignata
authors.forename: J S
authors.initials: JS
authors.lastname: Sanghera
authors.forename: R J
authors.initials: RJ
authors.lastname: Soiffer
authors.forename: S
authors.initials: S
authors.lastname: Chartier
authors.forename: M
authors.initials: M
authors.lastname: Eder
authors.forename: S L
authors.initials: SL
authors.lastname: Pelech
authors.forename: J
authors.initials: J
authors.lastname: Ritz
mesh_terms: D000328:Adult; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002453:Cell Cycle; D006801:Humans; D008213:Lymphocyte Activation; D008875:Middle Aged; D010750:Phosphoproteins / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D019000:Phosphotyrosine; D017871:Calcium-Calmodulin-Dependent Protein Kinases