Peter Lin

Introduction. Systemic Lupus Erythematosus (SLE) is a chronic autoimmune disease in which circulating autoantibodies and immune complexes deposit, activating the compliment system and causing local inflammation and tissue destruction throughout the body^1-2. SLE usually starts in late childhood to young adulthood, predominantly affecting females in reproductive years³. Dysfunction of T regulatory cells(Treg), which normally maintain immune homeostasis and prevent autoimmunity via self-tolerance, have been implicated in the development of SLE ^1,4. Research is underway to understand the mechanisms of T reg dysfunction. Methods. Sixty-one patients with SLE who met the criteria for SLE were enrolled. Purified Treg and Effector CD4 T cells were cultured without soluble OX40 ligand. The cells were then stained for Foxp3 expression. Next, antigen presenting cells (APC) that display surface OX40L were isolated from healthy patients and SLE patients, and cultured with T Reg cells and Effector CD4 T cells to measure T4 proliferation. A second study knocked out Egr2 (Early growth response gene) and double knocked out Egr2 and Egr3 in mice and measured the quantity of TGF-B3 produced by LAG3+ T reg cells. B cells were then stimulated in the absence and presence of TGF-B3, and the resulting immunoglobulin production concentration was measured. Results. When Treg wer ecultured with soluble OX40L, the Treg had a decreased Foxp3 expression, associated with induction of Effector CD4 T4 cell proliferation. CD4 T4 cells, when cultured with Antigen presenting cells of SLE patients, that display OX40L, exhibited significant proliferation in comparison to those cultured with APC of healthy donor patients ⁵. Egr2 and Egr2/egr3 knock out mice displayed significant decreases in quantity of TGF-B produced, with double knock out mice producing a negligible quantity. Stimulation of B cell in the presence of TGF-B produced significantly less immunoglobulins (IgA, IgG, IgM) than in the absence of TGF-B ^6,7. Conclusions. Surface OX40L directly suppresses the activity of Treg, leading to increased proliferation of effector CD4 T4 cells, mimicking immune dysregulation observed in SLE, with abundant proliferation of effector CD4 T cells, production of autoantibodies, and autoimmune disease. Egr2 and Egr3 are indirectly responsible for the production of TGF-B3 by LAG3+ Treg, which confer self-tolerance. Current clinical research involving SLE occurs at a downstream level, stimulating the IL-2 receptor of Treg to induce T-reg proliferation. OX40L and Egr2/Egr3 dysfunction may be great potential future targets in the treatment of SLE.

1. Scheinecker, C., Göschl, L., & Bonelli, M. (2019). Treg cells in health and autoimmune diseases: New insights from single cell analysis. Journal of Autoimmunity, 102376. doi: 10.1016/j.jaut.2019.102376
2. Tsokos, G. C., Lo, M. S., Reis, P. C., & Sullivan, K. E. (2016). New insights into the immunopathogenesis of systemic lupus erythematosus. Nature Reviews Rheumatology, 12(12), 716–730. doi: 10.1038/nrrheum.2016.186
3. Dörner, T., & Furie, R. (2019). Novel paradigms in systemic lupus erythematosus. The Lancet, 393(10188), 2344–2358. doi: 10.1016/s0140-6736(19)30546-x
4. Grant, C. R., Liberal, R., Mieli-Vergani, G., Vergani, D., & Longhi, M. S. (2015). Regulatory T-cells in autoimmune diseases: Challenges, controversies and—yet—unanswered questions. Autoimmunity Reviews, 14(2), 105–116. doi: 10.1016/j.autrev.2014.10.012
5. Jacquemin C, Augusto J-F, Scherlinger M, et al. OX40L/OX40 axis impairs follicular and natural Treg function in human SLE. JCI Insight. 2018;3(24). doi:10.1172/jci.insight.122167.
6. Okamura T, Sumitomo S, Morita K, et al. TGF-β3-expressing CD4 CD25−LAG3 regulatory T cells control humoral immune responses. Nature Communications. 2015;6(1). doi:10.1038/ncomms7329.
7. Morita K, Okamura T, Inoue M, et al. Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production. Proceedings of the National Academy of Sciences. 2016;113(50). doi:10.1073/pnas.1611286114
8. He J, Zhang X, Wei Y, et al. Low-dose interleukin-2 treatment selectively modulates CD4 T cell subsets in patients with systemic lupus erythematosus. Nature Medicine. 2016;22(9):991-993. doi:10.1038/nm.4148