Background Double-negative T cells (DNTs) are expanded in the peripheral blood of patients with Systemic Lupus Erythematosus (SLE) and in murine lupus models. DNTs are capable to produce IFN-y and TNF-α and are regarded as the major producers of IL-17 in SLE. They furthermore induce IgG and anti-DNA antibody production and contribute to tissue damage by infiltrating kidneys of SLE patients. Therefore DNTs critically contribute to pathogenesis and kidney damage in SLE. However, signals that drive migration, occurrence and pathogenic expansion of DNTs remain to be elucidated. B6/lpr mice represent a well-established murine lupus model and develop splenomegaly and lymphadenopathy, caused by a massive expansion of DNTs. In accordance with DNTs from SLE patients, DNTs in these mice produce IL-17, infiltrate the kidneys and contribute to nephritis.
Objectives We found high expression of CXCR5 on the surface of DNTs in lpr mice and therefore aimed to analyze, if CXCR5 directs migration of DNTs to spleens, lymph nodes and kidneys.
Methods B6/lpr CXCR5 deficient and B6/lpr wild type mice were analyzed anatomically. Surface cell markers were characterized by cell type analysis (flow cytometry) and germinal centers were analyzed in frozen spleen sections by fluorescence microscopy.
Results We generated B6/lpr mice which lack expression of CXCR5 (B6/lpr CXCR5-/- mice). CXCR5 deficient lpr mice developed reduced splenomegaly and lymphadenopathy paralleled by reduced levels of DNTs in these peripheral lymphoid organs, while DNT expression in the blood was unaltered. No germinal centers (GC) could be found in the spleens of these mice while B6/lpr wild type mice spontaneously developed GCs in the splenic follicles. Furthermore B6/lpr CXCR5-/- mice had a longer live time expectation compared to B6/lpr wild type mice.
Conclusions We therefore suggest that expression of CXCR5 on DNTs might contribute to their migration into lymphoid organs and to SLE pathogenesis and that the CXCR5/CXCL13 axis represents a target for therapeutic interventions.
Disclosure of Interest None declared