Journal Article

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

Sharabi, Amir, Tsokos, George C., Adamopoulos, Iannis E., Moon, James J., Moulton, Vaishali R., Stillman, Isaac E., Li, Hao, Herbert, Zach, Krishfield, Suzanne, Tsokos, Maria G.

2020

Overview

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. Splenic marginal zone macrophages can establish immune tolerance and limit the development of systemic lupus erythematosus (SLE). Here the authors show that these cells do this by clearing apoptotic cells, and defects in these cells result in the generation of self-reactive double negative T cells that are known to contribute to SLE pathogenesis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 38/1 / 631/250/1619/554 / 631/250/38 / 64/60 / 692/699/1670/1613 / Adoptive Transfer / Animals / Antigens / Apoptosis / Autoantigens / Autoantigens - immunology / Autoantigens - metabolism / CD4 antigen / CD8 antigen / Cell proliferation / Chronic conditions / Cytokines / Disease Models, Animal / Disease Progression / Female / Humanities and Social Sciences / Humans / Immune clearance / Immune Tolerance / Immunological tolerance / Interleukin 17 / Interleukin-17 - metabolism / Ki-67 Antigen - immunology / Ki-67 Antigen - metabolism / Lupus / Lupus Erythematosus, Systemic - blood / Lupus Erythematosus, Systemic - immunology / Lymphocytes / Lymphocytes T / Macrophages / Macrophages - immunology / Mice / Mice, Knockout / multidisciplinary / Pathogenesis / Receptors, Antigen, T-Cell, alpha-beta - metabolism / Science / Science (multidisciplinary) / Spleen / Systemic lupus erythematosus / T cell receptors / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism