Tolerogenic XCR1 + dendritic cell population is dysregulated in HLA-B27 transgenic rat model of spondyloarthritis

Abstract

Background: Spondyloarthritis (SpA) is a chronic inflammatory disease affecting primarily axial and peripheral joints and sometimes also extra-articular organs, such as the gut. Rats transgenic for HLA-B27 and human β2-microglobulin (B27-Tg rat) develop clinical manifestations resembling human disease. In this model, it has been shown that CD103 + conventional dendritic cells (cDCs) exhibited altered functions, likely promoting SpA development. CD4 - cDC subpopulation expressing XCR1, a chemokine receptor involved in their migration, have been described to be tolerogenic in steady state. Thus, in this study, we wished to examine the fate of XCR1 + cDCs in this animal model of SpA. Methods: cDC populations were isolated from the spleen, mesenteric lymph nodes (MLN), and colonic lamina propria from B27-TG and control nontransgenic (NTG) and/or HLA-B7 transgenic rats after collagenase digestion and density gradient and characterized with flow cytometry or real-time PCR. Migration of cDCs from intestinal mucosa to MLN was assessed, using TLR-7 stimulation with Resiquimod. Results: We observed a reduced frequency of cCD4 - DCs in B27-Tg rats, as compared to control rats. Furthermore, such decrease was not due to excessive death of CD4 - cDCs in B27-Tg rats. Interestingly, we observed a decrease frequency of the XCR1 + subpopulation among CD4 - cDCs in the spleen, MLN, and lamina propria from B27-Tg rats. Finally, after TLR-7 stimulation, the migration of XCR1 + cDCs to MLN was proportionally reduced in B27-Tg rats. Conclusion: Our results demonstrate for the first time a decreased proportion of the tolerogenic XCR1 + cDC subpopulation in SpA target organs in B27-Tg rat, which may affect the maintenance of self-tolerance and control of inflammation.