T Cells in Systemic Lupus Erythematosus

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Figure 1a: Normal calcium-mediated signaling through the T-cell receptor. In this simplified model, CD3ζ on the cell surface transmits signal via ZAP70, which leads to calcium influx and activation of calcineurin. Calcineurin dephosphorylates nuclear factor of activated transcription (NFAT, not shown here), a transcription factor that, in concert with other factors, mediates expression of IL-2. CREB also activates IL-2 transcription.

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Figure 1b: Model of T-cell signaling in SLE. In SLE T cells, CD3ζ is replaced by FcRγ, which signals through Syk rather than ZAP70. Although calcium signaling is stronger, transcription of IL-2 is lower than in normal T cells. CREM, rather than CREB, binds to the IL-2 promoter to repress transcription.

T-Cell Signaling Abnormalities: Gene Expression

There appear to be many explanations for why T cells from SLE patients express lower levels of CD3ζ. These include decreased transcription, decreased mRNA stability, alternative splicing, and increased protein degradation. For example, the CD3ζ gene promoter contains a cyclic AMP response element (CRE). The CRE-modulator (CREM) transcription factor binds to this element, repressing CD3ζ transcription. The IL-2 gene promoter also contains a CRE site; CREM represses IL-2 transcription in a similar manner. In contrast, the CRE-binding protein (CREB) also binds to the same CRE site, but acts as an activator of IL-2 transcription. SLE T cells show simultaneously increased CREM expression and decreased CREB activity.⁴ Taking together data from these experiments, it appears that this CREB/CREM imbalance in SLE T cells at least partially explains the decreased CD3ζ and IL-2 expression in these cells.

Correcting the CREB/CREM imbalance (and by translation, the defect in CD3ζ and IL-2) opens up a new area for therapeutic intervention. CREM expression is regulated in part by a calcium-responsive kinase, the calmodulin-dependent kinase IV (CaMK IV), and SLE patients show higher levels of CaMK IV in the nucleus. Interestingly, KN-93, a small molecule inhibitor of CaMK IV, has shown efficacy in treating mouse models of lupus, suggesting a promising area for investigation of new therapy.⁵

Functional Abnormalities of T Cells in SLE

Similar to the situation with T-cell signaling, studies have identified a variety of defects in T-cell function in SLE. For example, cytotoxic activity of CD8 T cells from SLE patients is diminished.⁶ An inability to suppress infected cells may lead to ongoing polyclonal B-cell activation and autoantibody production; furthermore, a defect in cell killing may also explain the predisposition of SLE patients towards macrophage activation syndrome. The potential consequences of decreased IL-2 production in SLE are not completely known but are likely to be many, given the many functions of IL-2 in regulating immune responses.