POS0010 CD38+ MEMORY T CELLS ARE A FUNCTIONALLY DISTINCT SUBSET THAT IS EXPANDED IN SLE AND ASSOCIATED WITH LUPUS NEPHRITIS
Authors: L. Ostendorf, P. Garantziotis, D. L. Wagner, P. Durek, F. Heinrich, P. Enghard, G. R. Burmester, A. Radbruch, M. F. Mashreghi, F. Hiepe, T. Alexander
Journal: Annals of the Rheumatic Diseases (2021)

Background: We recently reported the beneficial clinical responses of the anti-CD38 monoclonal antibody daratumumab in two patients with systemic lupus erythematosus (SLE) [1]. While the primary rationale for its use was the depletion of autoantibody-producing long-lived plasma cells, daratumumab may promote additional therapeutic effects on CD38-expressing T cells, but their origin, lifestyle and role in lupus pathophysiology remains elusive. Objectives: To investigate the phenotype, transcriptional program, functional properties and clinical associations of CD4+ and CD8+CD38+ memory T cells in SLE compared to healthy controls (HC). Methods: CD38-expression on memory T cell subsets was measured by flow cytometry in 65 patients with SLE and 28 healthy controls. We investigated the functional capacity of CD38+ T cells using CFSE staining and intracellular cytokine staining after polyclonal stimulation. Additionally, we performed single-cell transcriptome and T-cell-receptor sequencing of 7 SLE patients and 7 matched healthy controls, including surface protein expression analysis using CITE-seq (RNA-barcoded) antibodies. Results: Compared to healthy controls, the frequency of CD38-expressing memory T cells in SLE was significantly increased in both CD4+ and CD8+ T cells. SLE patients with a previous or current lupus nephritis had significantly increased levels of CD8+CD38+ memory T cells compared to those without history of renal involvement. CD38+ memory T cells expressed increased levels of Ki-67 and displayed higher proliferative capacity upon polyclonal stimulation than their CD38- counterparts, both in SLE patients and HC, while they showed decreased ability to secrete IFN-γ, IL-2, GM-CSF and TNF-α. Single-cell transcriptome sequencing revealed that CD8+CD38+ memory T cells were enriched within terminally differentiated, cytotoxic CD8 T cells, and had reduced TCR repertoire diversity compared to their CD38- counterparts. CD8+CD38+ memory T cells from SLE patients had significantly higher expression of type I interferon associated genes, both compared to CD38- memory T cells from SLE patients and CD38+ cells from HCs. Conclusion: CD38+ memory T cells with increased proliferative capacity but altered effector functions are significantly expanded in peripheral blood of SLE and correlate with the lupus nephritis. Although the factors mediating their generation and their precise role in the disease pathophysiology remain to be investigated, CD38-expressing T cells may be useful as a future biomarker for lupus nephritis. References: [1]Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N Engl J Med. 2020 Sep 17;383(12):1149–55. [2]Katsuyama E, Suarez-Fueyo A, Bradley SJ, Mizui M, Marin AV, Mulki L, et al. The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections. Cell Reports. 2020 Jan;30(1):112-123.e4. Acknowledgements: We thank our patients and healthy controls for making our research possible. Disclosure of Interests: None declared.