Double negative (DN) T cells are expanded in patients with systemic lupus erythematosus (SLE) and stimulate autoantibody production as efficiently as CD4+ T cells. In this study, we demonstrate that DN T cells from patients with SLE produce significant amounts of IL-17 and IFN-γ, and expand when stimulated in vitro with an anti-CD3 Ab in the presence of accessory cells. Furthermore, IL-17+ and DN T cells are found in kidney biopsies of patients with lupus nephritis. Our findings establish that DN T cells produce the inflammatory cytokines IL-17 and IFN-γ, and suggest that they contribute to the pathogenesis of kidney damage in patients with SLE.

Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system, and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal, and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review novel information that deals with 1) genes associated with disease expression, 2) immune cell molecular abnormalities that lead to autoimmune pathology, 3) the role of hormones and sex chromosomes in the development of disease, 4) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we emphasize molecular defects intimately associated with the disease process of SLE that represent ideal therapeutic targets and disease biomarkers.

T cells contribute to the initiation and perpetuation of autoimmunity in systemic lupus erythematosus (SLE), and seem to be directly involved in the development of related organ pathology. Defects associated with CD8 + and T-regulatory (T REG ) cell function manifest in parallel with the expanded CD3 + CD4 − CD8 − T cell lineage. The cytokine expression pattern is uniquely characterized by decreased expression of interleukin (IL)-2 and increased production of IL-17 and related cytokines. Therapeutic approaches that limit the cognate interaction between T cells and B cells, prevent inappropriate tissue homing and restore T REG cell function and the normal cytokine milieu have been entertained. Biochemical characterization of SLE T cells has revealed distinct early and late signaling aberrations, and has enabled the identification of novel molecular targets that can be corrected with small molecules, and biomarkers that may foretell disease activity and predict organ damage.

Immune homeostasis depends on the proper function of regulatory T (Treg) cells. Compromised Treg cell suppressive activity leads to autoimmune disease, graft rejection and promotes anti-tumor immunity. Here we report the previously unrecognized requirement of the serine/threonine phosphatase Protein Phosphatase 2A (PP2A) for the function of Treg cells. Treg cells exhibited high PP2A activity and Treg cell-specific ablation of the PP2A complex resulted in a severe, multi-organ, lymphoproliferative autoimmune disorder. Mass spectrometric analysis revealed that PP2A associates with components of the mTOR pathway and suppresses mTORC1 activity. In the absence of PP2A, Treg cells altered their metabolic and cytokine profile and were unable to suppress effector immune responses. Therefore, PP2A is requisite for the function of Treg cells and the prevention of autoimmunity.

Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17-producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17-producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.

The origin and function of human double negative (DN) TCR-αβ+ T cells is unknown. They are thought to contribute to the pathogenesis of systemic lupus erythematosus because they expand and accumulate in inflamed organs. In this study, we provide evidence that human TCR-αβ+ CD4− CD8− DN T cells can derive from activated CD8+ T cells. Freshly isolated TCR-αβ+ DN T cells display a distinct gene expression and cytokine production profile. DN cells isolated from peripheral blood as well as DN cells derived in vitro from CD8+ T cells produce a defined array of proinflammatory mediators that includes IL-1β, IL-17, IFN-γ, CXCL3, and CXCL2. These results indicate that, upon activation, CD8+ T cells have the capacity to acquire a distinct phenotype that grants them inflammatory capacity.

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Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune activation and tissue damage. Organ damage in SLE results from the deposition of immune complexes and the infiltration of activated T cells into susceptible organs. Cytokines are intimately involved in every step of the SLE pathogenesis. Defective immune regulation and uncontrolled lymphocyte activation, as well as increased antigen presenting cell maturation are all influenced by cytokines. Moreover, expansion of local immune responses as well as tissue infiltration by pathogenic cells is instigated by cytokines. In this review, we describe the main cytokine abnormalities reported in SLE and discuss the mechanisms that drive their aberrant production as well as the pathogenic pathways that their presence promotes.