THU0035 A cd8 alpha-negative subset of cd4+slamf7+ cytotoxic t cells is expanded in patients with igg4-related disease and decreases following glucocorticoid treatment
Authors: E. Della Torre, E. Bozzalla Cassione, C. Sciorati, M. Lanzillotta, E. Bozzolo, L. Rovati, H. Mattoo, C. Perugino, J. Stone, L. Dagna, S. Pillai, A. Manfredi
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> IgG4-Related Disease (IgG4-RD) is a fibro-inflammatory disorder characterised by tumefactive lesions, frequent elevation of serum IgG4 levels, and tissue fibrosis.<sup>1</sup> Glucocorticoids represent the treatment of choice to induce IgG4-RD remission but their effect on the cells orchestrating the disease remains unknown.<sup>1</sup> We recently describerd an unconventional population of clonally expanded CD4<sup>+</sup>SLAMF7<sup>+</sup> cytotoxic T effector memory (T<sub>EM</sub>) cells (CD4<sup>+</sup>CTLs) and causally linked it to IgG4-RD in view of their capacity to secrete pro-fibrotic molecules and to infiltrate affected organs.<sup>2–4</sup> <h3>Objectives</h3> In order to better clarify the mechanisms of action of glucocorticoids in IgG4-RD and the pathogenic relevance of CD4<sup>+</sup> CTLs, we herein aim to describe the effects of corticosteroid treatment on CD4<sup>+</sup> CTLs. <h3>Methods</h3> CD8α, granzyme A, perforin, and SLAMF7 expression within the effector/memory compartment of CD45RO (T<sub>EM</sub>) and CD45RA (T<sub>EMRA</sub>) CD4<sup>+</sup> T cells was quantified by flow cytometry in 18 active IgG4-RD patients at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T-cell receptor α and β chain gene was performed on circulating CD4<sup>+</sup>CTLs in patients with IgG4-RD before and after treatment, and in affected tissues. <h3>Results</h3> Circulating CD4<sup>+</sup> T<sub>EM</sub> and T<sub>EMRA</sub> cells were not expanded in IgG4-RD patients compared to healthy controls. CD4<sup>+</sup>SLAMF7<sup>+</sup> T<sub>EM</sub> cells (but not T<sub>EMRA</sub> cells) were significantly increased among IgG4-RD patients. Within CD4<sup>+</sup>SLAMF7<sup>+</sup> T<sub>EM</sub> cells, CD8α<sup>-</sup> but not CD8α<sup>low</sup> cells were elevated in IgG4-RD patients. The same dominant clones of CD8α<sup>-</sup>CD4<sup>+</sup>SLAMF7<sup>+</sup> T<sub>EM</sub> cells found in the peripheral blood were also identified in affected tissue. Both CD8α<sup>-</sup> and CD8α<sup>low</sup> CD4<sup>+</sup>SLAMF7<sup>+</sup> T<sub>EM</sub> cells expressed cytolytic molecules. Clonally expanded CD8α<sup>-</sup> but not CD8α<sup>low</sup> CD4<sup>+</sup>SLAMF7<sup>+</sup> T<sub>EM</sub> cells decreased following glucocorticoid-induced disease remission. <h3>Conclusions</h3> A subset of CD8α<sup>-</sup>CD4<sup>+</sup>SLAMF7<sup>+</sup> cytotoxic T<sub>EM</sub> cells is oligoclonally expanded in patients with active IgG4-RD. This population contracts following glucocorticoid-induced remission. Further characterisation of this cell population may provide prognostic information and targets for therapeutic intervention. <h3>References</h3> [1] Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol. 2015;1881:191–206. [2] Mattoo H, Della-Torre E, Mahajan VS, Stone JH, Pillai, S. Circulating Th2 memory cells in IgG4-Related Disease are restricted to a defined subset of subjects with atopy. Allergy2014;69:399–402. [3] Mattoo H, Mahajan VS, Maehara T, Deshpande V, Della-Torre E, Wallace ZS, et al. Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-Related DIsease. J Allergy Clin Immuno. 2016;138:825–38. [4] Maehara T, MAttoo H, Ohta M, Mahajan VS, Moriyama M, Yamauchi M, et al. Lesional CD4+ IFN-γ+ cytotoxic T lymphocytes in IgG4-Related DIsease dacryoadenitis and sialoadenitis. Ann Rheum Dis. 2017;76:377–385. <h3>Acknowledgements</h3> Fondazione Italiana per la Ricerca sull'Artrite (FIRA Onlus) <h3>Disclosure of Interest</h3> None declared