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Departments of Medicine (Rheumatology Division) and Microbiology-Immunology, Northwestern University Medical School, Chicago, IL 60611
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.
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