The clinical significance of decreased T cell interleukin-2 production in systemic lupus erythematosus: connecting historical dots.

Although decreased T cell production of interleukin-2 (IL-2) in systemic lupus erythematosus (SLE) was first described more than 25 years ago, questions concerning the significance of this observation and the causative mechanisms remain unresolved. IL-2 is now known to be a critical cytokine for the maintenance of immunologic homeostasis and tolerance to self antigens. Whether the production defect precedes SLE, is secondary to it, or reflects a compensatory attempt to reduce disease activity is not well understood. The article by Song et al, which is published in this issue of Arthritis & Rheumatism, addresses this issue and presents evidence of an acquired T cell defect that is a consequence of the disease (1). These investigators have previously reported that anti–double-stranded DNA (anti-dsDNA) antibodies can penetrate T cells and cause decreased production of IL-2. They now report the mechanism of this effect. Here, I briefly review the principal effects of IL-2 on the immune system, comment on the studies by Song et al in the context of previous studies on IL-2 production in SLE, and conclude with the view that both humoral and cellular mechanisms contribute to an acquired, ineffective, compensatory attempt to control pathologic T cell and B cell hyperactivity in active SLE. IL-2 is a multifunctional cytokine that was first described as a T cell growth factor. Decreased IL-2 production results in various T cell defects, which include impaired cell-mediated immunity associated with enhanced susceptibility to infections, reduced activationinduced cell death, and prolonged survival of autoreactive T cells. Insufficient IL-2 also results in loss of tolerance to self antigens. Tolerance is maintained by regulatory T cells that express the forkhead transcription factor FoxP3. IL-2 is essential for the generation and survival of CD4 FoxP3 regulatory cells that control potentially pathogenic self-reactive T cells (2). Normally, IL-2 produced by activated T cells expands and sustains the Treg cells, which maintain normal immune homeostasis. IL-2 signaling up-regulates STAT-5, two proteins (STAT-5A and STAT-5B) which enhance Treg generation and suppress Th17 differentiation (3), events that are critical in blocking the pathogenesis of lupus nephritis. Thus, it is probably not a coincidence that both decreased IL-2 production and T regulatory dysfunction are observed in SLE (4). Decreased IL-2 production strongly contributes to the generation of T cell– dependent pathogenic antinuclear antibodies and the subsequent development of clinical SLE. The pathogenicity of anti-DNA antibodies is associated with their polyreactivity with diverse antigens. When anti-DNA antibodies bind extracellular antigens directly or in the form of immune complexes, they can induce inflammatory cascades. Convincing evidence now exists that they can also penetrate living cells and alter function. In 1978, Alarcon-Segovia and coworkers reported that anti-DNA and anti-RNP antibodies could enter cells and interact with their intracellular target (5). Although at first, this was a subject of controversy, this work has been confirmed by several groups of investigators who documented that these antibodies can either enhance cell growth and proliferation or induce death and apoptosis, as described in the review by Putterman (6). Sun and colleagues have shown that charged monoclonal anti-DNA antibodies derived from MRL-lpr/lpr mice could penetrate living cells by electrostatic interactions and induce human T cells to produce several proinflammatory cytokines, including IL-1 , tumor necrosis factor , and IL-6 (7). Importantly, these antibodies also inhibited the production of IL-2. In this issue of Arthritis & Rheumatism, the latest contribution from Sun’s group, the report by Song et al, David A. Horwitz, MD: University of Southern California, Los Angeles. Address correspondence and reprint requests to David A. Horwitz, MD, Division of Rheumatology, Department of Medicine, University of Southern California, Keck School of Medicine, 2011 Zonal Avenue, HMR 711, Los Angeles, CA 90033. E-mail: dhorwitz@usc.edu. Submitted for publication April 20, 2010; accepted April 20, 2010.