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.

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.

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^lowCD4+SLAMF7+ T_EM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8α^lowCD4+SLAMF7+ T_EM cells decreased following glucocorticoid‐induced disease remission.

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.