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Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease.

ABSTRACT: BACKGROUND:Follicular helper CD4+ T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7+CD4+ T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4+ T (Th), particularly Tfh, cells and SLAMF7+ CD4+ T cells in IgG4-RD. RESULTS:The patients with IgG4-RD enrolled in this study were aged 66?±?12?years and their titers of serum IgG4 were 372?±?336?mg/dl. Th1 cells, activated circulating Tfh1 (cTfh1), and activated cTfh2 cells increased in IgG4-RD. SLAMF7 was mainly expressed on Th1 and cTfh1, but not cTfh2, cells in the patients. SLAMF7+ cTfh1 cells were PD-1/CD28 double-positive, whereas SLAMF7+ Th1 cells were CD28 negative. Positive correlations were noted between serum IgG4 levels and the number of activated cTfh2 cells and SLAMF7+ cTfh1 cells, but not SLAMF7+ Th1 cells. Intriguingly, among cTfh1 cells, activated SLAMF7+ cTfh1 cells were high producers of IL-10 along with IL-21. Blimp-1, but not Bcl-6, mRNA was expressed at high levels in activated SLAMF7+ cTfh1 cells. In addition to CD4+ T cells, the frequency of SLAMF7+ fraction was higher in memory B cells than naïve B cells in patients with IgG4RD. Finally, upon stimulation via B-cell receptor and CD40, Tfh1-associated cytokines, IL-21 and IFN-?, most significantly induced SLAMF7 expression in memory B cells. CONCLUSIONS:Together, these results suggest that circulating SLAMF7+ Tfh1 cells, along with Tfh2 cells, play a pathologic role in IgG4 production in IgG4-RD.

SUBMITTER: Higashioka K

PROVIDER: S-EPMC7268355 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Association of circulating SLAMF7<sup>+</sup>Tfh1 cells with IgG4 levels in patients with IgG4-related disease.

Higashioka Kazuhiko K Ota Yuri Y Maehara Takashi T Moriyama Masafumi M Ayano Masahiro M Mitoma Hiroki H Akahoshi Mitsuteru M Arinobu Yojiro Y Horiuchi Takahiko T Nakamura Seiji S Akashi Koichi K Niiro Hiroaki H

BMC immunology 20200601 1

<h4>Background</h4>Follicular helper CD4<sup>+</sup> T (Tfh) cells have a critical role in IgG4 production by B cells in IgG4-related disease (IgG4-RD). Recent studies including ours showed that SLAMF7<sup>+</sup>CD4<sup>+</sup> T cells are an important pathological driver of IgG4-RD. In this study, we have sought to elucidate a relationship between helper CD4<sup>+</sup> T (Th), particularly Tfh, cells and SLAMF7<sup>+</sup> CD4<sup>+</sup> T cells in IgG4-RD.<h4>Results</h4>The patients with I ...[more]

PMID: 32487061

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Project description: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 CD8αlow CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α- but not CD8αlow CD4+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.

Dataset Information

Association of circulating SLAMF7+Tfh1 cells with IgG4 levels in patients with IgG4-related disease.

Publications

Association of circulating SLAMF7<sup>+</sup>Tfh1 cells with IgG4 levels in patients with IgG4-related disease.

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