A1.20 Lymphoid tissue analyses in autoantibody positive individuals at risk for developing rheumatoid arthritis reveals an important role for CD8<sup>+</sup>T cells during the earliest phases of autoimmunity
Authors: TH Ramwadhdoebe, J Hähnlein, BJ van Kuijk, IY Choi, DM Gerlag, PP Tak, LGM van Baarsen
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background and objective</h3> The role of CD8<sup>+</sup> T cells in autoimmune disease is poorly understood and may depend on the phase of disease. CD8<sup>+</sup> T cells can contribute to autoimmunity by driving inflammation through cytokine release, tissue infiltration and cytotoxic T cell (CTL) function or by dampening the immune response through CD8<sup>+</sup> regulatory T cells. To provide more insight into the role of CD8<sup>+</sup> T cells during the development of autoimmune disease, we investigated the phenotype and function of CD8<sup>+</sup> T cells in lymphoid tissue and peripheral blood during the earliest phases of rheumatoid arthritis (RA). <h3>Methods</h3> We collected inguinal lymph node biopsies and peripheral blood from 20 individuals with arthralgia but without arthritis, who were positive for IgM rheumatoid factor (IgM-RF) and/or anti-citrullinated protein antibodies (ACPA; RA-risk individuals); 17 early RA patients; and 19 healthy controls (HCs). CD8<sup>+</sup> T cell function and phenotype were analysed using flow cytometry. To measure cytokine production cells were stimulated for four hours with PMA/Ionomycin in the presence of Brefeldin A and Golgi stop. <h3>Results</h3> We found higher frequencies of lymphoid memory CD8<sup>+</sup>CD45RO<sup>+</sup> T cells in RA-risk individuals (p &lt; 0.05) and early RA patients (p &lt; 0.05) compared with HCs. In addition, we found higher frequencies of activated lymphoid CD8<sup>+</sup>CD45RA<sup>+</sup>CD69<sup>+</sup> T cells in early RA patients compared with HCs (p &lt; 0.05). Interleukin-(IL-)10 and interferon gamma (IFNg) production in lymphoid CD8<sup>+</sup> T cells was decreased in the RA risk individuals compared with HCs (p &lt; 0.01). There was a decrease in both IFNg and IL-17A production in lymphoid CD8<sup>+</sup> T cells in early RA patients (p &lt; 0.05). We did not detect changes in frequencies of cytotoxic effector CD8<sup>+</sup> T cells in peripheral blood or lymphoid tissue during the earliest phases of RA. In lymphoid tissue of early RA patients there was a negative correlation between the CD8<sup>+</sup>IL-17A<sup>+</sup> mean fluorescent intensity (MFI) and disease activity score in 28 joints (DAS28) (p = 0.005, r = -0.81) and swollen joint count 28 (SJC28; p = 0.01, r = -0.76) and between CD8<sup>+</sup>IL-10<sup>+</sup>MFI and DAS28 (p = 0.05, r = -0.67) and tender joint count 28 (TJC28; p = 0.02, r = -0.73). These data indicate that a decrease in lymphoid tissue derived regulatory and pro-inflammatory cytokines was related to disease activity. <h3>Conclusion</h3> The data present here suggest that CD8<sup>+</sup> T cells exhibit an exhaustive phenotype during the RA-risk phase and earliest phases of RA, which might be explained by continuous antigen presentation and CD8<sup>+</sup> T cell activation.