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

Y. Yi, M. McNerney, S. K. Datta*

*Corresponding author for this work

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

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 Ca2+ → 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.

Original languageEnglish (US)
Pages (from-to)6627-6634
Number of pages8
JournalJournal of Immunology
Volume165
Issue number11
DOIs
Publication statusPublished - Dec 1 2000

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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