Systemic lupus erythematosus favors the generation of IL-17 producing double negative T cells

Hao Li, Iannis E. Adamopoulos, Vaishali R. Moulton, Isaac E. Stillman, Zach Herbert, James J. Moon, Amir Sharabi, Suzanne Krishfield, Maria G. Tsokos and George C. Tsokos ()
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Hao Li: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Iannis E. Adamopoulos: Division of Rheumatology, Allergy and Clinical Immunology, University of California
Vaishali R. Moulton: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Isaac E. Stillman: Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School
Zach Herbert: Molecular Biology Core Facilities, Dana-Farber Cancer Institute
James J. Moon: Center for Immunology and inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School
Amir Sharabi: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Suzanne Krishfield: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
Maria G. Tsokos: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School
George C. Tsokos: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract Mature double negative (DN) T cells are a population of αβ T cells that lack CD4 and CD8 coreceptors and contribute to systemic lupus erythematosus (SLE). The splenic marginal zone macrophages (MZMs) are important for establishing immune tolerance, and loss of their number or function contributes to the progression of SLE. Here we show that loss of MZMs impairs the tolerogenic clearance of apoptotic cells and alters the serum cytokine profile, which in turn provokes the generation of DN T cells from self-reactive CD8+ T cells. Increased Ki67 expression, narrowed TCR V-beta repertoire usage and diluted T-cell receptor excision circles confirm that DN T cells from lupus-prone mice and patients with SLE undergo clonal proliferation and expansion in a self-antigen dependent manner, which supports the shared mechanisms for their generation. Collectively, our results provide a link between the loss of MZMs and the expansion of DN T cells, and indicate possible strategies to prevent the development of SLE.

Date: 2020
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DOI: 10.1038/s41467-020-16636-4

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