AB1111 GLYCOSYLATION OF γδT CELLS AS AN ESSENTIAL PLAYER IN THE IMMUNOPATHOGENESIS OF SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: B. Santos-Pereira, I. Alves, A. Campar, A. Marinho, C. Vasconcelos, S. Pinho
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic Lupus Erythematosus (SLE) is a chronic and complex autoimmune disease characterized by the loss of self-tolerance associated with a broad spectrum of clinical manifestations, being still an incurable disease<sup>1</sup>. Protein glycosylation is a major post-translational modification that defines the activity and function of immune cells. Changes in cellular glycosylation patterns have been identified by others and us in autoimmune diseases<sup>3,4,5</sup>. Recently, we have described that a unique subset of γδT cells were involved in SLE immunopathogenesis, by recognizing abnormal cellular glycosylation patterns of kidney epithelial cells<sup>4</sup>. <h3>Objectives:</h3> Despite recent studies, it remains completely unknown the impact of γδT cells' glycosylation profile in defining their response. In this study, we aim to explore the biological impact of γδT cells' <i>N</i>-glycosylation in regulating its' activity and function as a potential new mechanism in SLE immunopathogenesis. <h3>Methods:</h3> We have characterized, through flow cytometry, the glycosylation profile of immune cells from the peripheral blood of SLE patients, and conducted a RNA-seq analysis of published available data from γδT cells glycogenes expression in healthy individuals. Moreover, to study the biological impact of altered glycans in γδT cells´ function, we conducted <i>in vitro</i> studies by taking advantage of different conditional glycoengineered mice models with altered glycans in γδT cells. Finally, to disclose the impact of glycans in SLE disease, we induced a lupus-like disease (pristane-induced) in a specific glycoengineered mice model. <h3>Results:</h3> We have shown that the glyco-signature of γδT cells from the peripheral blood of SLE patients display an altered composition of <i>N</i>-glycans that can be related to their activity and function. In accordance, the RNA-seq analysis of healthy individuals revealed a dependency of γδT cells on the expression levels of some glycogenes, suggesting that altered glycans in these cells might contribute to altered response. In addition, we also demonstrated that selected γδT cells glycosylation patterns result in a hyperactive and proinflammatory response that might contribute to SLE disease. Interestingly, we showed that abnormal glycosylation of γδT cells was associated with an increased susceptibility to pristane-induced lupus mice model, which was correlated with increased infiltration of γδT cells in the kidney and increased proteinuria and anti-dsDNA levels. <h3>Conclusion:</h3> Overall, this work highlights the importance of glycosylation in defining γδT cell response, proposing a potential and novel-target-specific mechanism involved in the immunopathogenesis of SLE disease. <h3>REFERENCES:</h3> [1] Tsokos GC et al. Nat Rev Rheumatol. 2016 Nov 22;12(12):716–30. [2] Pereira MS &amp; Alves I. et al. Front Immunol. 2018 Nov 27;9:2754. [3] Dias AM et al. Proc Natl Acad Sci U S A. 2018 May 15;115(20):E4651–60. [4] Alves I, et al. Science Translational Medicine. 2023 15(687), eabo1930. [5] Pereira, M et al. Clinical and Translational Gastroenterology 11 4 (2020): e00166 <h3>Acknowledgements:</h3> This work was funded by 2022 Lupus Innovation Award (funded by Lupus Research Alliance) and acknowledges Portuguese Foundation for Science and Technology (FCT) for funding (2022.00337.CEECIND; and UI/BD/151550/2021). <h3>Disclosure of Interests:</h3> <b>None declared.</b>