SAT0033 Smoking contributes to exhausted state of CD4+ T cells in rheumatoid arthritis
Authors: C Wasén, M Turkkila, M Erlandsson, KM Andersson, M Brisslert, S Töyrä Silfverswärd, MI Bokarewa
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Rheumatoid arthritis (RA) has recently been linked to an exhausted state of CD4<sup>+</sup> T cells in peripheral blood of patients [1]. Exhaustion of CD4<sup>+</sup> T cells limits their proliferation and increases cell death. In CD8<sup>+</sup> T cells smoking counteract exhaustion, which may lead to increased cytotoxic activity exemplified by targeting of cells with high expression of the anti-apoptotic protein survivin [2]. Exhaustion of CD4<sup>+</sup> T cells coincides with expression of interferon (IFN) response genes [3], referred to as the IFN signature. The development of the IFN signature has been suggested to predate RA [4]. <h3>Objectives</h3> We investigated how smoking affect the CD4<sup>+</sup> T cell population in peripheral blood of RA patients with focus on the exhaustion marker programmed cell death-1 (PD-1). <h3>Methods</h3> Blood samples were collected from RA patients and healthy women with different smoking status and analysed for PD-1 and survivin expression using flow cytometry and qPCR. Sorted Th17 cells from peripheral blood were analysed for expression of 18 genes up regulated during exhaustion [3], herein referred to as the exhaustion set, and serum levels of survivin were assessed by ELISA. Peripheral blood CD4+ cells were analysed for their expression of seven IFN response genes [4]. The role of survivin in the formation of exhausted CD4<sup>+</sup> T cells was studied in collagen-induced arthritis (CIA), where mice were treated with nicotine or vaccinated with survivin peptides. <h3>Results</h3> High frequency of exhausted PD-1<sup>+</sup>CD4<sup>+</sup> cells was found in smoking RA patients. The numbers of PD1<sup>+</sup>CD4<sup>+</sup> cells correlated inversely with the PD-1 expression by cytotoxic CD8<sup>+</sup>CD107<sup>+</sup> cells (r=-0.62, p=0.01). Additionally, the frequency of PD-1<sup>+</sup>CD4<sup>+</sup> cells increased with reduction of the CD4<sup>+</sup> population (r=-0.71, p=0.002). The IFN signature was found exclusively among smoking RA patients. The patients with the IFN signature all had CD4<sup>+</sup> cells with low survivin production. Th17 cells from RA patients with high serum survivin were enriched in genes of the exhaustion set. CD4<sup>+</sup> cells with high survivin expression were negative for PD-1, while PD-1<sup>hi</sup> cells had low expression of survivin. In CIA mice the survivin<sup>hi</sup>PD-1<sup>-</sup> CD4<sup>+</sup> cells were reduced by nicotine treatment (p=0.03) or survivin vaccination (p=0.009). <h3>Conclusions</h3> Smoking associates with exhaustion of CD4<sup>+</sup> T cells in RA by increasing the frequency of PD-1<sup>+</sup>CD4<sup>+</sup> cells and supporting the IFN signature. Balancing T cell exhaustion and preventing the IFN signature are potential future treatment strategies for RA. <h3>References</h3> Frenz T, et al. J Allergy Clin Immunol 2016. 138(2): 586–589. Wasén C, et al. J Autoimmun 2017. DOI: 10.1016/j.jaut.2016.12.00. Crawford A, et al. Immunity 2014. 40(2): 289–302. Lübbers J, et al. Ann Rheum Dis 2013. 72(5): 776–780. <h3>Disclosure of Interest</h3> None declared