LAUSR

Background: Various alterations of the peripheral T-cell compartment have been reported in granulomatosis with polyangiitis (GPA) such as elevated populations of CD4+CD8+ double-positive and CD4+CD161+ and CD28- single-positive effector memory T-cells (TEM) within the total CD3+ T-cell population (1). Analysis of antigen-specific T-cell subpopulations shows, that PR3-specific T-cells display Th2-type, Th17 and Th22 cytokine profiles in GPA (2). Moreover, concomitant cellular CMV- and Epstein Barr virus (EBV)-infection has been found to be associated with the expansion of CD28- TEM in GPA (1,2). Notably, C-type lectin CD161+CD8+ T-cells displaying a polyfunctional memory profile directed against several common viruses have been reported. Furthermore, CD161+ T-cells are involved in the pathogenesis of early stage autoimmune hepatitis (3). CD161 expression on proteinase 3 (PR3)-specific T-cells in comparison to other antigen-specific T-cells has not been described in GPA as yet. Objectives: To determine the amount of C-type lectin CD161 on antigen-specific CD8+ single-positive and CD4+CD8+ double positive T-cells in patients with GPA Methods: In this study, we analyzed the expression of CD161 and CD28 on circulating antigen-specific CD8+ single-positive and CD4+CD8+ double positive T-cells in HLA-A2 positive patients with GPA (n=21) and healthy controls (n=21) using flow cytometry. Antigen-specific T cells were detected using peptide/MHC class 1 dextramers containing major peptide epitopes for PR3, Epstein Barr virus (EBV) BMLF1, and Cytomegalovirus (CMV) pp65 (aa 196-177, aa 280-288, and aa 495-504, respectively). Results: Patients with GPA showed a higher frequency of circulating CD8+ single-positive and CD4+CD8+double-positive PR3-specific T-cells with increased expressions of CD161 compared to HC. Compared to EBV- or CMV-specific T-cells, there was an increased expression of CD161 on PR3-specific T-cells in GPA. In contrast to HC and EBV- or CMV-specific T-cells, the percentage of CD28+ T-cells was expanded within the PR3-specific CD8+ T-cell subset in GPA. Conclusion: These findings suggest a potential role of CD161 as an additional TCR-independent co-stimulatory receptor on PR3-specific T-cells in GPA. The role of these cells in the pathophysiology and as a potential therapeutic target remains be further investigated. References [1] Kerstein A, et al., Environmental factors and inflammation-driven alteration of the total peripheral T-cell compartment in granulomatosis with polyangiitis; J Autoimmun. 2017Mar;78-79-91 [2] Lamprecht P, et al., Pathogenetic and clinical aspects of anti-neutrophil cytoplasmatic autoantibody associated vasculitis. Front. Immunol. 2018; 9:680 [3] Renand A, et al. Immune alterations in patinents with type 1 autoimmune hepatitis persist upon standard immunosuppressive treatment. Hepatol Commun. 2018 Aug 6;2(8):868-981 Disclosure of Interests: Sebastian Klapa: None declared, Anja Kerstein: None declared, Andreas Koch: None declared, Silke Pitann: None declared, Relana Nieberding: None declared, Gabriela Riemekasten Consultant for: Chugai, F. Hoffmann-La Roche, Speakers bureau: Chugai, F. Hoffmann-La Roche, Antje Müller: None declared, Peter Lamprecht: None declared