Abstract
Expansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE). Here we show expression of an orphan immune regulator, death receptor 6 (DR6/TNFRSF21), on a population of Tfh cells that are highly expanded in lupus-like disease progression in mice. Genome-wide screening reveals an interaction between syndecan-1 and DR6 resulting in immunosuppressive functions. Importantly, syndecan-1 is expressed specifically on autoreactive germinal centre (GC) B cells that are critical for maintenance of Tfh cells. Syndecan-1 expression level on GC B cells is associated with Tfh cell expansion and disease progression in lupus-prone mouse strains. In addition, Tfh cell suppression by DR6-specific monoclonal antibody delays disease progression in lupus-prone mice. These findings suggest that the DR6/syndecan-1 axis regulates aberrant GC reactions and could be a therapeutic target for autoimmune diseases such as SLE.
Highlights
Expansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE)
Recent independent studies have reported that upregulation of the TNFRSF21 gene is associated with disease prognosis by genomewide gene expression analysis using peripheral mononuclear cells obtained from SLE patients[25,26]
25-1 antibody (25-1 Ab) bound DR6 stably expressed on L929 cells (L929-mDR6) (Supplementary Fig. 1a). 25-1 Abs bound to DR6, but not to other TNFRSF molecules that were expressed on the cell surface (Supplementary Fig. 1b). 25-1 Abs could bind to endogenous DR6, expressed by murine T cell hybridoma (DO11.10-T) cells (Supplementary Fig. 1c, left panel), and this reactivity was lost after Tnfrsf[21] gene-specific knockout based on the CRISPR-Cas[9] system (G510-8-7 or -10-4) (Supplementary Fig. 1c, middle and right panels), indicating that 25-1 Abs react with endogenous DR6 but not the other proteins expressed on the cell (Supplementary Fig. 1c,d)
Summary
Expansion of autoreactive follicular helper T (Tfh) cells is tightly restricted to prevent induction of autoantibody-dependent immunological diseases, such as systemic lupus erythematosus (SLE). Tfh cell suppression by DR6-specific monoclonal antibody delays disease progression in lupus-prone mice These findings suggest that the DR6/syndecan-1 axis regulates aberrant GC reactions and could be a therapeutic target for autoimmune diseases such as SLE. A functional blockade or defect in negative costimulatory molecules, including programmed cell death 1 (PD1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4), induces an aberrant GC reaction and systemic autoimmunological disease[13,14,15,16]. These findings indicate that during T/B cell interactions, costimulatory molecules fine-tune Tfh cell differentiation, preventing the induction of systemic autoimmunity. Syndecan-1 may act as a scaffold for soluble factors, inducing the accumulation of inflammatory cells in localized inflammation[27]
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