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

Abstract

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 CD8α, 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 α- and β-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, CD8α- cells but not CD8α^low cells were elevated in IgG4-RD patients. The same dominant clones of CD8α-CD4+SLAMF7+ T_EM cells found in peripheral blood were also identified in affected tissue. CD8α- and CD8α^low CD4+SLAMF7+ T_EM cells both expressed cytolytic molecules. Clonally expanded CD8α- but not CD8α^low CD4+SLAMF7+ T_EM cells decreased following glucocorticoid-induced disease remission.

Conclusion: A subset of CD8α-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.