Session Type: ACR Abstract Session
Session Time: 2:30PM-4:00PM
Background/Purpose: Enthesis-resident CD4-CD8- double-negative (DN) T cells have been implicated in the pathogenesis of spondyloarthritis. Overexpression of IL-23 in adult mice activates these cells to produce IL-17A and other pathogenic cytokines leading to spondyloarthritis-like disease. Many innate lymphocytes require IL-1 for IL-23-induced production of IL-17A in vitro. We therefore investigated the role of IL-1 receptor signals on CD4-CD8- DN T cell homeostasis and induction of murine spondyloarthritis.
Methods: Lymphocytes were isolated from the spleen and Achilles enthesis of wildtype, Il23r-/-, Il1r1-/- and Il23r-gfp reporter mice (C57BL/6 background) and analyzed in vitro. Disease was induced by hydrodynamic injection of IL-23 minicircles (System Biosciences) in B10.RIII mice. To block IL-1 signals, animals were injected ip. with a cocktail of three monoclonal antibodies against IL-1α, IL-1β and IL-1R1. Animals were monitored every other day for arthritis development. Animals were euthanized two weeks after disease induction for tissue harvest and analysis.
Results: Enthesial CD4-CD8- DN T cells comprise γδ T cells and DN αβ T cells. Both γδ T cells and DN αβ T cells secreted IL-17A upon in vitro stimulation with IL-23 + IL-1β but not IL-23 alone. Cell frequencies were not substantially different in Il23r-/- or Il1r1-/- mice compared with wildtype mice. Disease induction in Il1r1-/- mice could not be tested as C57BL/6 wildtype mice do not develop arthritis upon IL-23 minicircle injection. Antibody blockade of IL-1 signals in susceptible B10.RIII mice had no impact on disease incidence but ameliorated arthritis severity.
Conclusion: IL-23 and IL-1 receptor signals control the function but not the development of enthesial γδ T cells and DN αβ T cells. Antibody-mediated blockade of IL-1 in susceptible B10.RIII mice reduced arthritis severity but not disease incidence suggesting that mediators other than IL-1 may provide a second signal for IL-23-induced IL-17A production in vivo. The lack of arthritis development in C57BL/6 mice injected with IL-23 minicircles diminishes the utility of this model for studies of spondyloarthritis pathogenesis.
To cite this abstract in AMA style:Matmusaev M, Haley E, Hossain I, Ermann J. Cytokine Dependence of Enthesis-resident Lymphocytes in Murine Spondyloarthritis [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/cytokine-dependence-of-enthesis-resident-lymphocytes-in-murine-spondyloarthritis/. Accessed November 29, 2020.
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