A cd8 alpha-negative subset of cd4+slamf7+ cytotoxic t cells is expanded in patients with igg4-related disease and decreases following glucocorticoid treatment

Background: IgG4-Related Disease (IgG4-RD) is a fibro-inflammatory disorder characterised by tumefactive lesions, frequent elevation of serum IgG4 levels, and tissue fibrosis.1 Glucocorticoids represent the treatment of choice to induce IgG4-RD remission but their effect on the cells orchestrating the disease remains unknown.1 We recently describerd an unconventional population of clonally expanded CD4+SLAMF7+ cytotoxic T effector memory (TEM) cells (CD4+CTLs) and causally linked it to IgG4-RD in view of their capacity to secrete pro-fibrotic molecules and to infiltrate affected organs.2–4Objectives: In order to better clarify the mechanisms of action of glucocorticoids in IgG4-RD and the pathogenic relevance of CD4+ CTLs, we herein aim to describe the effects of corticosteroid treatment on CD4+ CTLs.Methods: CD8α, granzyme A, perforin, and SLAMF7 expression within the effector/memory compartment of CD45RO (TEM) and CD45RA (TEMRA) CD4+ 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+CTLs in patients with IgG4-RD before and after treatment, and in affected tissues.Results: Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEM cells, CD8α- but not CD8αlow cells were elevated in IgG4-RD patients. The same dominant clones of CD8α-CD4+SLAMF7+ TEM cells found in the peripheral blood were also identified in affected tissue. Both CD8α- and CD8αlow CD4+SLAMF7+ TEM cells expressed cytolytic molecules. Clonally expanded CD8α- but not CD8αlow CD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission.Conclusions: A subset of CD8α-CD4+SLAMF7+ cytotoxic TEM 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.