Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells.
To identify intrinsic defects in lupus, we studied short-term, CD4(+) T cell lines that were established from 16 lupus patients (active or inactive) and 15 normal subjects by stimulating once with anti-CD3, anti-CD28, and IL-2. After resting, the pure CD4(+) T cells were exposed to anergy-inducing stimulation with plate-bound anti-CD3 mAb in the absence of APC. Lupus T cells showed prolonged high level expression of CD40 ligand (CD40L, CD154) even in the face of anergy protocol, which shut down CD40L expression in normal T cells. The sustained CD40L expression in lupus T cells did not correlate with memory status or Th deviation, and was relatively independent of IL-2 or other autocrine or paracrine signals via CD28 or CTLA-4. Cyclosporin A could block CD40L expression by lupus T cells when added early during the anti-CD3 stimulation period, but only partially when added later, indicating that another mechanism regulates the prolonged hyperexpression of CD40L besides the Ca(2+) --> calcineurin-dependent NF-AT pathway. When exposed to the anergy protocol, lupus T cells, in marked contrast to normal T cells, did not phosphorylate Cbl/Cbl-b but continued to express strongly phosphorylated extracellular signal-regulated kinase (ERK); U0126, a specific inhibitor of mitogen-activated protein kinase kinase --> ERK, could block both the early and the prolonged hyperexpression of CD40L. Thus, pathways regulating the activities of Cbl and one particular mitogen-activated protein kinase, ERK, are involved in the prolonged hyperexpression of CD40L in lupus T cells.
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Department of Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
McNerney
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Datta
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D000069594:Abatacept; D000293:Adolescent; D000328:Adult; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D023201:CD40 Ligand / Q000096:biosynthesis*; D060908:CTLA-4 Antigen; D019703:Calcineurin / Q000502:physiology; D002460:Cell Line; D017635:Clonal Anergy; D004268:DNA-Binding Proteins / Q000502:physiology; D004789:Enzyme Activation / Q000276:immunology; D005260:Female; D006801:Humans; D007113:Immunity, Innate; D018796:Immunoconjugates; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000502:physiology; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D050721:Proto-Oncogene Proteins c-cbl; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology* / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D014157:Transcription Factors / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D004268:DNA-Binding Proteins; D018796:Immunoconjugates; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D014157:Transcription Factors; D023201:CD40 Ligand; D014443:Tyrosine; D000069594:Abatacept; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D020928:Mitogen-Activated Protein Kinases; D019703:Calcineurin; C067419:CBL protein, human