Regulation of Transcription Determines Interleukin 2 Deficiency in Sle T Cells

Interleukin-2 (IL-2) represents a crucial cytokine in the activation of lymphocytes. IL-2 exerts multiple functions, which serve both the promotion and the suppression of the immune response (Nelson, 2004). Fine-tuning of the production of this cytokine is the result of numerous interrelated events, which make its study a complex but intriguing task. Reduction in IL-2 production in SLE T cells upon stimulation was first documented in the 1980s, when PHA-primed cells from lupus patients produced less IL-2 compared to normal T cells (Linker-Israeli et al., 1983), and it was later on associated with the decreased immune responses to infectious agents encountered in patients with SLE.

IL-2 deficiency in SLE T cells is the result of transcriptional repression of the IL-2 gene. Study of transcriptional regulation of IL-2 in normal T cells has shown that the decisive elements for the transcription of the molecule lie within 300 bp upstream of the start codon of the IL-2 gene promoter (Jain et al., 1995). Within these 300 bp several AP-1 sites are found, which are closely related to adjacent NFAT sites, as well as an NFkB, a C-responsive element (RE) and a CD28-RE site. Currently, defects leading to decreased IL-2 production in SLE T cells include changes in the expression and function of the transcription factors NFkB, AP-1, CREM, and CREB (Figure 19.1).

In SLE T cells NFkB activity is decreased due to deficiency of its p65 subunit (Wong et al., 1999). Under physiologic conditions, the p65/p50 heterodimer accounts for the NFKB-mediated IL-2 upregulation (Jain et al., 1995). Conversely, SLE T cells express adequate amounts of p50, which in the absence of p65 homodimerize, conveying a repressor effect (Wong et al., 1999). The importance of p65 deficiency is furthermore supported by experiments showing

Interleukin - 2 gene promoter CREM/


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