Background/Purpose:

Type I (IFN-α) and type II (IFN-γ) interferons are important mediators of autoimmunity. However, there is conflicting evidence regarding the contribution of IFN-γ to the pathogenesis of RA. We recently showed a strong association of IFN-γ receptor 1 (Ifngr1) expression and of IFN-γ receptor 2 (Ifngr2) expression in peripheral blood mononuclear cells (PBMC) with the presence of RA and its radiographic severity, respectively (Arthritis Rheumatol. 2015 67:1165). IL-2 has essential regulatory function in inflammatory diseases and is considered as a potential therapy for autoimmune disease. In this study, we tested the hypothesis that RA is associated with alterations in IFN-γ and IL-2 STAT signaling within certain subsets of PBMCs.

Methods:

We used a high-definition phospho-flow approach to evaluate the activation of STAT1 (assessed using antibody to phosphorylated tyrosine at position 701 [pY701]), STAT3 (pY705) and STAT5 (pY694) after stimulation with IFN-γ or IL-2. We analyzed subsets of PBMCs from 35 RA patients and 12 healthy controls (HC) as shown in Table.

Table. Subsets of PBMCs analyzed in this study.

Results:

We found that IFN-γ induced STAT1 activation was significantly greater in naïve, central memory, Tfh and Treg subsets of CD4+ T cell populations from RA patients compared to HC (p<0.05). IFN-γ induced STAT1 activation in RA was similar to HC in effector memory CD4 T cells, all CD8 T cell populations, B cells and monocytes. Phosphatases dephosphorylate STATs to regulate the activation of cytokine induced signals. We found that phenyl-arsine oxide (PAO), a broadly active phosphatase inhibitor, had no effect on IFN-γ induced STAT1 activation in any T cell population from RA or HC. This result indicates that IFN-γ induced acute activation of STAT1 is not regulated by a phosphatase in RA or HC. IFN-γ did not activate STAT3 any mononuclear cell population among RA or HC. IL-2 very efficiently activated STAT5 in all T and B cell populations in RA and HC. The activation of STAT5 in RA was significantly greater than HC in only one population: effector memory CD4 T cells (p<0.01). Remarkably, treatment with PAO greatly enhanced IL-2 induced activation of STAT5 in RA, but not HC CD4 T cell populations (naïve, central memory effector memory, Treg, Tfh). PAO had no effect on STAT5 activation in CD8 T cell populations from RA and HC. This result suggests that the regulatory activity of IL-2 in RA CD4 T cell populations is attenuated by a STAT5-specific phosphatase.

Conclusion:

Our results indicate that CD4 T cell subpopulation dependent enhanced IFN-γ STAT1 signals and attenuated IL2-STAT5 signals (possibly due to a phosphatase inhibitor) contribute to the pathogenesis of RA. Future studies will focus on stratifying patients by disease activity and other covariates.

« Back to 2017 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/enhanced-ifn-%ce%b3-stat1-signaling-in-cd4-t-cell-populations-and-attenuated-il-2-stat5-signaling-contribute-to-the-pathogenesis-of-rheumatoid-arthritis-ra/