P033/O31 CD38-expressing memory T cells are expanded in peripheral blood, contained in inflamed tissue and represent a potential treatment target in systemic lupus erythematosus

Career situation of first and presenting author Student for a master or a PhD. Introduction The unresponsiveness of long-lived plasma cells (PC) to immunosuppressive and B cell depleting therapies represents a therapeutic challenge in systemic lupus erythematosus (SLE) and other immune-mediated diseases. Novel potential targets such as CD38 have emerged.1 Objectives Here, we aimed to analyze expression levels of CD38 on circulating plasmablast and peripheral blood and tissue residing lymphocyte subsets in SLE to estimate the therapeutic potential of CD38-targeting therapies. Methods Multicolor flow cytometry was performed to investigate the CD38 expression on peripheral blood mononuclear cells (PBMCs) of SLE patients (n=36), healthy controls (HC, n=20) and multiple myeloma (MM, n=10) patients. In addition, kidney-infiltrating T cells isolated from urine were analyzed in patients with lupus nephritis (LN). To investigate the cytokine secreting potential, cytokines were analyzed intracellularly in CD38-expressing T cells after polyclonal stimulation in vitro with PMA/Ionomycin. Results Circulating CD19+CD24negCD27high plasmablasts are more frequent in SLE and MM patients and display higher mean fluorescence intensity for CD38 compared to HC. In SLE, CD38 is significantly higher expressed in both CCR7+ central and CCR7neg effector memory CD4 and CD8 T cells compared to HC. Such cells co-express other markers of T cell activation and recent proliferative history such as HLA-DR and Ki-67, and are preferentially negative for FoxP3 and Helios. CD38 is most exclusively expressed on CXCR3+ memory T cells isolated from urine of patients with LN in contrast to their CXCR3neg counterparts. Upon polyclonal stimulation, cytokine (IFN-g, IL-17, TNFa, IL-2) secreting cells were confined to memory T cells lacking CD38 expression. Conclusions Expression levels of CD38 are significantly higher in peripheral blood memory B- and T-cell subsets from patients with SLE compared to HC. CD38pos T cells co-express markers of recent activation and proliferative history, are confined to conventional memory T cells and contained in inflamed tissue, suggesting a pathogenic role of a chronically activated memory T cell compartment in SLE. The lack of effector cytokine secretion of such cells is unexpected and merits further investigation. PC depleting therapies targeting CD38 may represent a promising treatment option in SLE given their potential therapeutic effect on activated memory T cells in inflamed tissue. Reference Hiepe F, Radbruch A. Nat Rev Nephrol 2016. Acknowledgements We thank all study participants and blood donors. Disclosure of Interest None declared.