FRI0266 ABERRANT PD-1 AND VISTA EXPRESSION ON CD4+ TH-CELLS IN GIANT CELL ARTERITIS
Authors: Rebeca Hid Cadena, Rosanne Reitsema, Wayel Abdulahad, Minke G. Huitema, Annemieke Boots, Peter Heeringa, Elisabeth Brouwer
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The immune system controls immune responses by balancing positive and negative immune checkpoint (IC) molecules in cell-cell interactions. These co-stimulatory and co-inhibitory molecules allow complete T-cell activation and T-cell effector functions giving rise to an optimal immune response while preventing autoimmunity (1). Failure of tolerance results in the initiation and propagation of pathogenic T-cell responses leading to the development of autoimmune diseases such as Giant Cell Arteritis (GCA). The latter is a complex illness of multiple pathogenic factors with important contributions of both innate and adaptive immunity in its initiation and perpetuation (2,3). Recently, a loss of inhibitory checkpoints on immune cells has been implicated in the immunopathology of GCA (4,5). The possible contribution of IC pathways to the dysregulation of Th-cells in GCA could aid in our understanding of GCA immunopathology. <h3>Objectives:</h3> In this study, we aimed to investigate the expression of different IC molecules and their ligands by circulating monocytes, and functionally distinct populations of CD4+T-cells in peripheral blood samples from GCA-patients in comparison to healthy controls (HCs). <h3>Methods:</h3> In a cross-sectional study, fresh blood samples were obtained from 30 GCA-patients with/without immunosuppressive treatment (glucocorticoids) and 18 sex and age-matched HCs. The frequency of the expression of different IC including CD80/86, PD-L1, PDL2 and V-domain Ig suppressor of T-cell activation (VISTA) were determined on total monocytes and subsets (classical, intermediate and non-classical). In parallel, expression of the corresponding receptors CD28, Cytotoxic T-Lymphocyte-associated antigen-4 (CTLA-4), Programmed death- 1 (PD-1), and VISTA were determined on total CD4+ and subsets of Th-cells defined by CD45RA and CD25 expression of GCA-patients and HCs by flow cytometry. <h3>Results:</h3> The frequencies of CD80/CD86+ and VISTA+ monocytes were decreased in GCA-patients compared to HCs. Proportions of circulating CD4+ Th-cells in GCA-patients were not different when compared to HCs. The frequencies of CD28 and CTLA-4 expressing CD4+Th-cells did not differ between GCA-patients and HCs. In contrast, proportions of PD-1 and VISTA expressing Th-cells were significantly decreased in GCA patients. Memory T-cells showed decreased expression of IC molecules. Interestingly, naïve T-cell populations already demonstrated loss of PD-1 and VISTA. <h3>Conclusion:</h3> In GCA, lower frequencies of CD80/CD86+ and VISTA+ circulating monocytes were found. Likewise, decreased proportions of PD-1+CD4+ and VISTA+CD4+ Th-cells were noted. Decrease of negative IC on the surface of immune cells could add to the persistent activation of CD4+T-cells seen in GCA. <h3>References:</h3> [1] Ceeraz S, Nowak EC, Noelle RJ. B7 family checkpoint regulators in immune regulation and disease. Trends in Immunology. 2013. [2] Samson M, Corbera-Bellalta M, Audia S, Planas-Rigol E, Martin L, Cid MC, et al. Recent advances in our understanding of giant cell arteritis pathogenesis. Autoimmun Rev[Internet]. 2017Aug;16(8):833–44. [3] Weyand CM, Goronzy JJ. Immune mechanisms in medium and large-vessel vasculitis. Nat Rev Rheumatol. 2013;9(12):731–40. [4] Watanabe R, Zhang H, Berry G, Goronzy JJ, Weyand CM. Immune checkpoint dysfunction in large and medium vessel vasculitis. Am J Physiol - Hear Circ Physiol [Internet].2017May1;312(5):H1052–9. [5] Zhang H, Watanabe R, Berry GJ, Vaglio A, Liao YJ, Warrington KJ, et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc Natl Acad Sci {United States of America} [Internet]. 2017;201616848. <h3>Acknowledgement:</h3> Special thanks to the Vasculitis Expertise Center Groningen <h3>Disclosure of Interests:</h3> Rebeca Hid Cadena: None declared, Rosanne Reitsema: None declared, Wayel Abdulahad: None declared, Minke G. Huitema: None declared, Annemieke Boots Grant/research support from: grant from MSD in 2010-2015, Consultant for: I was a consultant for Grunenthal Germany 2016-2017, Employee of: I was an employee of Organon, Shering-Plough and MSD from 1991-2011, Peter Heeringa: None declared, Elisabeth Brouwer Speakers bureau: Dr. Brouwer as an employee of the UMCG received speaker fees and consulting fees from Roche which were paid to the UMCG