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.

Yi Y, McNerney M, Datta SK
J Immunol. 2000 165 (11): 6627-34

PMID: 11086108 · DOI:10.4049/jimmunol.165.11.6627

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.

MeSH Terms (35)

Abatacept Adolescent Adult Antigens, CD Antigens, Differentiation Calcineurin CD28 Antigens CD40 Ligand Cell Line Clonal Anergy CTLA-4 Antigen DNA-Binding Proteins Enzyme Activation Female Humans Immunity, Innate Immunoconjugates Immunologic Memory Interleukin-2 Lupus Erythematosus, Systemic Male MAP Kinase Signaling System Middle Aged Mitogen-Activated Protein Kinases NFATC Transcription Factors Nuclear Proteins Phosphorylation Proto-Oncogene Proteins Proto-Oncogene Proteins c-cbl Receptors, Antigen, T-Cell T-Lymphocytes T-Lymphocytes, Helper-Inducer Transcription Factors Tyrosine Ubiquitin-Protein Ligases

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