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

E Della-Torre, E Bozzalla-Cassione, C Sciorati, E Ruggiero, M Lanzillotta, S Bonfiglio, H Mattoo, CA Perugino, E Bozzolo, L Rovati, PG Arcidiacono, G Balzano, D Lazarevic, C Bonini, M Falconi, JH Stone, L Dagna, S Pillai, AA Manfredi

Research output: Contribution to journalArticle

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+ TEMand TEMRAcells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEMcells (but not TEMRAcells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEMcells, CD8α− cells but not CD8αlowcells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEMcells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEMcells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEMcells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEMcells is oligoclonally expanded in patients with active IgG4-RD. This TEMcell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. © 2018, American College of Rheumatology
Original languageEnglish
Pages (from-to)1133-1143
Number of pages11
JournalArthritis and Rheumatology
Volume70
Issue number7
DOIs
Publication statusPublished - 2018

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Glucocorticoids
Immunoglobulin G
T-Lymphocytes
Cytotoxic T-Lymphocytes
Therapeutics
Population
T-Cell Receptor Genes
Granzymes
Perforin
Contracts
Healthy Volunteers
Flow Cytometry
Clone Cells

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A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment. / Della-Torre, E; Bozzalla-Cassione, E; Sciorati, C; Ruggiero, E; Lanzillotta, M; Bonfiglio, S; Mattoo, H; Perugino, CA; Bozzolo, E; Rovati, L; Arcidiacono, PG; Balzano, G; Lazarevic, D; Bonini, C; Falconi, M; Stone, JH; Dagna, L; Pillai, S; Manfredi, AA.

In: Arthritis and Rheumatology, Vol. 70, No. 7, 2018, p. 1133-1143.

Research output: Contribution to journalArticle

@article{57aa16fa78964706bbfb28b56368b161,
title = "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 (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+ TEMand TEMRAcells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEMcells (but not TEMRAcells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEMcells, CD8α− cells but not CD8αlowcells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEMcells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEMcells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEMcells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEMcells is oligoclonally expanded in patients with active IgG4-RD. This TEMcell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. {\circledC} 2018, American College of Rheumatology",
author = "E Della-Torre and E Bozzalla-Cassione and C Sciorati and E Ruggiero and M Lanzillotta and S Bonfiglio and H Mattoo and CA Perugino and E Bozzolo and L Rovati and PG Arcidiacono and G Balzano and D Lazarevic and C Bonini and M Falconi and JH Stone and L Dagna and S Pillai and AA Manfredi",
year = "2018",
doi = "10.1002/art.40469",
language = "English",
volume = "70",
pages = "1133--1143",
journal = "Arthritis and Rheumatology",
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}

TY - JOUR

T1 - A CD8α− Subset of CD4+SLAMF7+ Cytotoxic T Cells Is Expanded in Patients With IgG4-Related Disease and Decreases Following Glucocorticoid Treatment

AU - Della-Torre, E

AU - Bozzalla-Cassione, E

AU - Sciorati, C

AU - Ruggiero, E

AU - Lanzillotta, M

AU - Bonfiglio, S

AU - Mattoo, H

AU - Perugino, CA

AU - Bozzolo, E

AU - Rovati, L

AU - Arcidiacono, PG

AU - Balzano, G

AU - Lazarevic, D

AU - Bonini, C

AU - Falconi, M

AU - Stone, JH

AU - Dagna, L

AU - Pillai, S

AU - Manfredi, AA

PY - 2018

Y1 - 2018

N2 - 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+ TEMand TEMRAcells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEMcells (but not TEMRAcells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEMcells, CD8α− cells but not CD8αlowcells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEMcells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEMcells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEMcells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEMcells is oligoclonally expanded in patients with active IgG4-RD. This TEMcell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. © 2018, American College of Rheumatology

AB - 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+ TEMand TEMRAcells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEMcells (but not TEMRAcells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEMcells, CD8α− cells but not CD8αlowcells were elevated in IgG4-RD patients. The same dominant clones of CD8α−CD4+SLAMF7+ TEMcells found in peripheral blood were also identified in affected tissue. CD8α− and CD8αlowCD4+SLAMF7+ TEMcells both expressed cytolytic molecules. Clonally expanded CD8α− but not CD8αlowCD4+SLAMF7+ TEMcells decreased following glucocorticoid-induced disease remission. Conclusion: A subset of CD8α−CD4+SLAMF7+ cytotoxic TEMcells is oligoclonally expanded in patients with active IgG4-RD. This TEMcell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention. © 2018, American College of Rheumatology

U2 - 10.1002/art.40469

DO - 10.1002/art.40469

M3 - Article

VL - 70

SP - 1133

EP - 1143

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 7

ER -