Systemic lupus erythematosus (SLE) afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While the overall survival and quality of life has improved during the last 30 years, we still lack specific treatmen, full understanding of the involved pathogenic mechanisms and proper disease biomarkers. T cells missing CD4 and CD8 from the surface (CD3+CD4-CD8-) are expanded in patients with SLE and they can help autologous B cells to produce autoantibodies, produce interleukin-17 and infiltrate tissue to instigate inflammation. CD3+CD4-CD8- may arise from CD8+ cells following epigenetic closure of the CD8 locus. Building on data generated during the last cycle, this proposal will test the hypothesis that CD3+CD4-CD8- cells originate from CD8 cells upon encountering antigen, produce proinflammatory cytokines and enter target tissues. In three integrated but independent sets of experiments we will 1) define the epigenetic requirements that lead to the generation of CD3+CD4-CD8- cells in patients with SLE and lupus prone mice and further define their metabolic status; 2) determine how interleukin-2 suppresses and interleukin-17 expands the generation of DN cells in lupus-prone mice, and 3) study determinants of CD3+CD4-CD8- entry in to the kidney. The proposal introduces state-of-the-art techniques to 1) study the epigenetic closure of CD8 which leads to the expansion of CD3+CD4-CD8- cells, 2) understand their metabolic profile and 3) to visualize their entry in to the kidney. Conceptually, the studies introduce epigenetics and metabolomics to help understand the nature of pathogenic T cell subset in SLE patients. The proposed studies are significant because the numbers of circulating CD3+CD4-CD8- cells may represent a biomarker as they may enter tissues to cause damage and because control of their generation and metabolic profile and interference with their entry to tissues should reveal therapeutic options.
Systemic lupus erythematosus afflicts more than a million Americans, primarily women, and presents with symptoms resulting from the involvement of practically every organ. The origin of the disease involves diverse factors which probably contribute variably to the expression of the disease in each patient. Understanding the cellular abnormalities that lead to organ damage through this line of research will help us identify novel treatment targets and biomarkers.
|Moulton, Vaishali R; Suarez-Fueyo, Abel; Meidan, Esra et al. (2017) Pathogenesis of Human Systemic Lupus Erythematosus: A Cellular Perspective. Trends Mol Med 23:615-635|
|Dai, Hong; He, Fan; Tsokos, George C et al. (2017) IL-23 Limits the Production of IL-2 and Promotes Autoimmunity in Lupus. J Immunol 199:903-910|
|Rodríguez-Rodríguez, Noé; Apostolidis, Sokratis A; Fitzgerald, Lauren et al. (2016) Pro-inflammatory self-reactive T cells are found within murine TCR-??(+) CD4(-) CD8(-) PD-1(+) cells. Eur J Immunol 46:1383-91|
|Suárez-Fueyo, Abel; Bradley, Sean J; Tsokos, George C (2016) T cells in Systemic Lupus Erythematosus. Curr Opin Immunol 43:32-38|
|Moulton, Vaishali R; Tsokos, George C (2015) T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity. J Clin Invest 125:2220-7|
|Rodríguez-Rodríguez, Noé; Apostolidis, Sokratis A; Penaloza-MacMaster, Pablo et al. (2015) Programmed cell death 1 and Helios distinguish TCR-??+ double-negative (CD4-CD8-) T cells that derive from self-reactive CD8 T cells. J Immunol 194:4207-14|
|Hedrich, Christian M; Crispín, José C; Rauen, Thomas et al. (2014) cAMP responsive element modulator (CREM) ? mediates chromatin remodeling of CD8 during the generation of CD3+ CD4- CD8- T cells. J Biol Chem 289:2361-70|
|Mizui, Masayuki; Koga, Tomohiro; Lieberman, Linda A et al. (2014) IL-2 protects lupus-prone mice from multiple end-organ damage by limiting CD4-CD8- IL-17-producing T cells. J Immunol 193:2168-77|
|Koga, Tomohiro; Mizui, Masayuki; Yoshida, Nobuya et al. (2014) KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase IV, promotes generation and function of Foxp3? regulatory T cells in MRL/lpr mice. Autoimmunity 47:445-50|
|Kyttaris, Vasileios C; Kampagianni, Ourania; Tsokos, George C (2013) Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int 2013:861028|
Showing the most recent 10 out of 21 publications