P065 Insulin-like growth factor 1 receptor regulates the phenotype and function of CD21+ B cells

Background Ligand to the inducible T cell costimulator (ICOSL) on B cells is essential for the ICOS-dependent follicular recruitment of activated T cells. In patients with rheumatoid arthritis (RA) the IGF1-IGF1R axis is altered. Inhibition of IGF1R alleviated arthritis by reducing IL-6-dependent formation of Th17 cells.1 Here we study the role of IGF1R on CD21 +cells in experimental arthritis. Methods Female Balb/c mice were immunised with methylated BSA or with CII. Consequences of the IGF-1R inhibition for arthritis were studied in mBSA and CII-immunised mice treated with NT157 compound promoting degradation of insulin receptor substrates or using shRNA producing construct (shIGF1R). At termination three sub-populations of CD21 +cells were analysed: follicular dendritic cells (FDc, CD21 +CD19-CXCR5-); marginal zone B cells (MZBc, CD21 +CD19+CXCR5-); follicular B cells (FBc, CD21 +CD19+CXCR5+). Supernatants of LPS-stimulated splenocytes were analysed for production of cytokines, chemokines using Cytokine Array. Serum levels of antigen specific and autoantibodies were measured in an ELISA. Results In spleen of mBSA-immunised mice, ICOSL expression on CD21 +cells correlated to IGF1R (r=0.70, p=0.007). Inhibition of IGF1R induced a 20% reduction in ICOSL expression in all CD21 +subsets (p=0.007) followed by an increase in the number of MZBc (p=0.003), while FDc and FBc were unchanged. Inhibition of IGF1R had no effect on the expression of ICOS +on CD4 T cells or the subset of CXCR5 +follicular T cells. Reduction of the ICOSL +CD21+B cells was associated with lower production of IL-13. Inhibition of IGF1R signalling by NT157 and by shRNA, reduced production of CXCL13 and CXCL12, the chemokines essential for B cell migration towards follicules. In contrast, the production of chemokines CCL5 and CXCL12 preventing intra-follicular migration was increased, which explains the increase of MZBc. Additionally, the insufficient ICOSL signalling significantly reduced the production of IL-7 and IL-4, regulating class switching of B cells in germinal centres and differentiation of B cells into plasma cells. The described disbalance in the cytokines aiding B cell development led to the reduced production anti-inflammatory IL-10 and of mBSA-specific IgM (p=0.005) and increased production of autoreactive RF-IgM levels (p=0.001). Conclusions The study shows that IGF1R controls B cell development through the expression of ICOSL on CD21 +cells. Insufficient ICOSL signalling disturbs a balance between antigen-specific response and autoantibody production in experimental arthritis. Reference [1] Erlandsson MC, Toyra Silfversward S, Nadali M, Turkkila M, Svensson MND, Jonsson IM, et al. IGF-1R signalling contributes to IL-6 production and T cell dependent inflammation in rheumatoid arthritis. Biochim Biophys Acta. 2017;1863:2158–70. Disclosure of Interest None declared