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IL-2 plays a key role in setting the balance between immunity and tolerance. This cytokine has a dual role as the regulator of the two main phases of the immune response (proliferative and suppressive). Likewise, activation induced cell death and the induction and maintenance of regulatory T cells are the tolerance mechanisms regulated by IL-2, which convey the link between IL-2 abnormalities and the development of autoimmune disorders, such as systemic lupus erythematosus (SLE). Particularly, in SLE murine models and in humans, deficiency in IL-2 synthesis and activity has been proven. Diverse signaling pathways abnormalities (TCR, NF-kappaBeta, NF-AT) have been involved in the IL-2 transcriptional dysregulation displayed by T cells from SLE patients, and its functional relevance as part of the physiopathogenic scheme has been shown. Aberrant expression and activity of multiple IL-2 transcriptional factors, such as c-fos, and predominantly, CREM and CREB have been involved in this immune dysregulation. Diverse alterations in signaling kinases and phosphatases (PKA, PP2A, CAMKIV) and the modulation by epigenetic mechanisms have been related to the altered CREM/pCREB index. The synergic effect of multiple abnormalities in the transcriptional factors previously mentioned has been shown to be of functional relevance in lupus.

T cells from patients with systemic lupus erythematosus (SLE) display a number of biochemical abnormalities which include altered expression of key signaling molecules, heightened calcium responses, and skewed expression of transcription factors. These defects are involved in the altered behavior of SLE T cells and are probably central in the disease pathogenesis. The aim of this communication is to review the defects that have been consistently documented in SLE T cells, highlighting molecules and pathways that represent therapeutic targets.

The regulation of IL-2 production is central to our understanding of the immune system. Key during T cell activation, it also plays an essential role in the regulation of the immune response. This review discusses the function of recently described factors that modulate transcription and chromatin remodeling at the IL2 promoter. Also, it addresses the role of FoxP3 as a transcriptional regulator in conventional T cells and regulatory T cells, and the mechanisms whereby CD28 stabilizes IL2 transcription and translation. Finally, the alterations that prevent T cells from SLE patients from producing normal amounts of IL-2 upon stimulation are described.

Dendritic cells (DC) play a pivotal role in the development of immune responses and the maintenance of peripheral tolerance. They continuously patrol tissues and sample antigens in search for the presence of inflammatory or pathogen-derived signals; they mature in accordance to signs prevalent in their environment and, by doing so, acquire certain features that will allow them to convey a precise message — either productive or regulatory — to the T cells they will encounter within regional lymph nodes. Evidence suggests that DC are involved in the pathogenesis of SLE. Their capacity to induce an antinuclear-oriented autoimmune response has been proven in animal models. Further, their maturation process is abnormal and their cytokine secretion and T cell stimulation is biased in patients with SLE. Lupus, however, is a problematic environment for their study and characterization. Sera from SLE patients contain several factors capable of inducing phenotypic and functional changes in DC. Thus, the abnormalities that have been reported may represent DC-intrinsic defects, a skewed phenotype due to an abnormal milieu, or a combination of both. In this review we discuss the available information in an attempt to reconcile these issues.

The aim of this work was to discuss the current knowledge concerning regulatory T cells in the pathogenesis of autoimmune diseases. CD4 + T cells that constitutively express CD25 exhibit powerful suppressive properties. Such cells have been denominated regulatory T cells (T R ). Alterations in T R cells are known to cause organ-specific autoimmune disease in animal models. These cells are anergic when stimulated via their TCR but proliferate when costimulated with IL-2. A particular characteristic is that CD4 + CD25 + T cells inhibit the proliferative responses of CD4 + CD25 − T cells by suppressing the capacity of the responders to transcribe IL-2. The survival and/or expansion of this regulatory subset in the periphery appears to need the availability of IL-2, the components of the IL-2R, as well as cell surface costimulatory molecules. Cytokine participation has been shown in many of the in vivo models of autoimmunity where regulatory cells participate, providing evidence in favour of a role for IL-10, transforming growth factor-β and IL-4. The behavior and possible participation of regulatory T cells in human disease is still a poorly explored topic but their pathogenic role is warranted.