A CD8α- Subset of CD4+SLAMF7+Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment

Objective. An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (T-EM) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD. Methods. Expression of CD8, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (T-EM) and CD45RA+ effector memory T (T-EMRA) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor - and -chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues. Results. Circulating CD4+ T-EM and T-EMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ T-EM cells (but not T-EMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ T-EM cells, CD8- cells but not CD8(low) cells were elevated in IgG4-RD patients. The same dominant clones of CD8-CD4+SLAMF7+ T-EM cells found in peripheral blood were also identified in affected tissue. CD8- and CD8(low)CD4+SLAMF7+ T-EM cells both expressed cytolytic molecules. Clonally expanded CD8- but not CD8(low)CD4+SLAMF7+ T-EM cells decreased following glucocorticoid-induced disease remission. Conclusion. A subset of CD8-CD4+SLAMF7+ cytotoxic T-EM cells is oligoclonally expanded in patients with active IgG4-RD. This T-EM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.