Cytokines

IL-2

T cells from patients with SLE produce aberrantly low amounts of the vital cytokine IL-2. IL-2 is important in autoimmune disease because it is not only necessary for the proliferation and function of regulatory T (Treg) cells but also is vital for activation-induced cell death which is important for the deletion of autoreactive T cells. In addition, IL-2 is important for cell-mediated immunity, which is crucial, as patients with autoimmune disease are susceptible to infections either due to immunosuppressive therapy or due to dysregulated immune responses. Tregs qualified by the CD4+ CD25+ or CD4+CD25+FoxP3+ phenotype are impaired in proliferation in human autoimmune disease accounting for their reduced numbers and function. Studies in IL-2 and IL-2 receptor knockout mice have shown that these mice develop severe spontaneous autoimmune disease and succumb to lymphoproliferative disease. A deficiency of Treg cells in these mice is thought to account for the unchecked proliferation of lymphocytes leading to lymphadenopathy.

Whereas IL-2 production is reduced and is protective for autoimmunity, it has also been ascribed a pro-inflammatory role in selective target tissues rendering its role in disease is complicated. Whereas IL-2 knockout and FoxP3 deficient scurfy mice both develop multiorgan inflammation, the IL-2 knockout mice do not develop skin and lung inflammation. It was shown that IL-2 controls the migration and localization of both Th1 and Th2 CD4 T cells in an organ-specific manner. IL-2-deficient mice demonstrated a lack of trafficking receptors and Th2 cytokines (IL-4, IL-5, IL-13) important for skin and lung inflammation revealing a target organ specific pro-inflammatory role for IL-2.

IL-2 gene expression is controlled mainly at the transcriptional and post-transcriptional levels. Transcription factors NFAT, AP1, and NFκB among others are key factors, which bind to cognate sites within the IL-2 promoter ( Fig. 19.2 ). Upon T cell activation, TCR signaling induces intracellular signaling cascades that ultimately lead to the translocation of NFAT and NFκB into the nucleus and initiate transcription of IL-2. In SLE T cells, reduced amounts and activity of NFκB and AP1 are thought to contribute to lower IL-2 expression. Whereas NFAT is increased in SLE T cells, hence activating CD40L expression, NFAT in conjunction with AP1 is necessary for IL-2 transcriptional activation. Therefore, the lack of AP1 is important in the IL-2 defect. More recently an RNA binding protein SRSF1 was identified to play a role in IL-2 production by activating IL-2 transcription indirectly. SRSF1 expression was reduced in patients with SLE more so in patients with active disease. Interestingly, SRSF1 force expressed into SLE T cells rescued IL-2 production. In addition to these factors, a balance between the transcription factors cyclic AMP response element modulator (CREM) and CREB is important in IL-2 regulation ( Fig. 19.2 ). Both factors compete for binding to a CRE site at the − 180 position within the IL-2 promoter. In SLE T cells, disruption of this balance is thought to contribute to the reduced IL-2 expression. Protein kinase A (PKA) phosphorylates and PP2A dephosphorylates CREB. Reduced PKA activity and increased expression of the PP2A leads to reduced availability of pCREB. Increased expression of CREM is attributed to the increase in transcription mediated by the SP1 transcription factor and binding to the CREM promoter. CREM is phosphorylated by the calcium-regulated kinase CAMKIV. CAMKIV is increased in SLE T cells and therefore increased pCREM leads to IL-2 repression. Serum from SLE patients induced the increased binding of CREM to the IL-2 promoter through activation of CAMKIV, and T cells from MRL/lpr lupus-prone mice also showed increased levels of CAMKIV. CAMKIV inhibitor treatment was able to prevent and correct autoimmunity and disease pathology in lupus prone mice. It was also reported that downregulation of miR-200a-3p is involved in the hypoproduction of IL-2 in T cells from lupus-prone mice. IL-23 induces limited IL-2 production from lupus T cells in vitro, and T cells from IL-23 ^-/- MRL/lpr mice produce increased amounts of IL-2 suggesting that IL-23 limits the production of IL-2.

To expand Tregs, low-dose IL-2 therapy has been tried in lupus-prone mice and patients with SLE. Administration of IL-2 partially restores the number of Tregs in lymphoid organs and periphery in NZB/NZW F1 mice. There are some uncontrolled clinical trials of low-dose IL-2 therapy for patients with SLE. Although these studies suggest that low-dose IL-2 therapy could increase the number of Tregs and improve clinical features, further studies with larger number of patients are required. It should be noted that not only the production of IL-2 from T cells but also the response to exogenous IL-2 is impaired in CD4 T cells from SLE compared with healthy controls.