Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (TEM) 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+ (TEM) and CD45RA+ effector memory T (TEMRA) 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+ 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− cells but not CD8αlow cells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.
Della-Torre, E., Bozzalla-Cassione, E., Sciorati, C., Ruggiero, E., Lanzillotta, M., Bonfiglio, S., et al. (2018). A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment. ARTHRITIS & RHEUMATOLOGY, 70(7), 1133-1143 [10.1002/art.40469].
A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment
Rovati L.;
2018
Abstract
Objective: An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7–positive (SLAMF7+) cytotoxic effector memory T (TEM) 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+ (TEM) and CD45RA+ effector memory T (TEMRA) 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+ 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− cells but not CD8αlow cells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.
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