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

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

doi:10.1038/s41467-020-16636-4

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.

Highlights

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)
Our results suggest that the lack of marginal zone macrophages (MZMs) leads to the expansion of DN T cells in this lupus-prone mouse strain both in the spleen and the kidney and promotes disease development
The importance of expanded DN T cells has been exploited in several autoimmune diseases, including SLE34, autoimmune lymphoproliferative syndrome[41], Sjogren’s syndrome[42], and aplastic anemia[43], which are believed to be driven/exaggerated by autoantigens derived from uncleared apoptotic cell blebs[2,44]

Summary

Introduction

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. 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. 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. Among the prominent T-cell abnormalities which have been reported in patients with SLE are the expansion of pathogenic. Several lines of evidence suggest that DN T cells may arise from activated CD8 T cells[10,11,12,13,14], but the specific factors which promote

Methods

Results

Conclusion