Increased Production of Interleukin‐17 Over Interleukin‐10 by Treg Cells Implicates Inducible Costimulator Molecule in Experimental Spondyloarthritis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2014-09, Vol.66 (9), p.2412-2422
• Main Authors: Araujo, Luiza M., Fert, Ingrid, Jouhault, Quentin, Labroquère, Karine, Andrieu, Muriel, Chiocchia, Gilles, Breban, Maxime
• Format: Article
• Language: English
• Subjects: Animals; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cytokines; Dendritic Cells - immunology; Dendritic Cells - metabolism; Inducible T-Cell Co-Stimulator Protein - metabolism; Interleukin-10 - biosynthesis; Interleukin-17 - biosynthesis; Male; Rats; Rats, Transgenic; Rodents; Spondylarthritis - immunology; Spondylarthritis - metabolism; T cell receptors; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.38737

Objective HLA–B27/human β2‐microglobulin (hβ2m)–transgenic (B27‐transgenic) rats develop an inflammatory disorder resembling spondyloarthritis, with accumulation of proinflammatory Th17 cells. Because Treg cells and Th17 cells have opposing effects in inflammatory disorders, we sought to determine whether biased expansion of Th17 cells could result from altered Treg cell frequency and/or function in B27‐transgenic rats. Methods We characterized the phenotype and function of Treg cells from B27‐transgenic rats in comparison with those from control rats, by examining their expression of cell surface markers, suppressive activity, cytokine production, and differentiation pattern. Results In B27‐transgenic rats, the preferential accumulation of CD4+ Teff cells over Treg cells was not associated with a defect in Treg cell differentiation or suppressive activity. The expression of Treg cell markers was similar between B27‐transgenic and control rats, with the exception of the inducible costimulator (ICOS) molecule, which was overexpressed in B27‐transgenic rats. High levels of ICOS are considered to be a hallmark of Treg cells with heightened suppressive activity and interleukin‐10 (IL‐10) expression. Paradoxically, the production of IL‐10 by Treg cells was reduced in B27‐transgenic rats, whereas the production of IL‐17 was enhanced. Moreover, the addition of anti‐ICOS monoclonal antibodies during Treg cell differentiation in the presence of dendritic cells from B27‐transgenic rats reversed this cytokine profile, restoring the balance between IL‐10 and IL‐17 in Treg cells from B27‐transgenic rats. Conclusion We observed dysregulated production of IL‐10 and IL‐17 by Treg cells from B27‐transgenic rats, which may contribute to disease development. Moreover, our data highlight a key role for ICOS signaling in the generation of imbalanced production of IL‐10 and IL‐17 by Treg cells in this experimental model of spondyloarthritis.