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Increased expression and modulated regulatory activity of co-inhibitory receptors PD-1, TIGIT and TIM-3 in lymphocytes of systemic sclerosis patients.

Increased expression and modulated regulatory activity of co-inhibitory receptors PD-1, TIGIT and TIM-3 in lymphocytes of systemic sclerosis patients.
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Fleury M, Belkina AC, Proctor EA, Zammitti C, Simms RW, Lauffenburger DA, Snyder-Cappione JE, Lafyatis R, Dooms H,


Fleury M, Belkina AC, Proctor EA, Zammitti C, Simms RW, Lauffenburger DA, Snyder-Cappione JE, Lafyatis R, Dooms H, (click to view)

Fleury M, Belkina AC, Proctor EA, Zammitti C, Simms RW, Lauffenburger DA, Snyder-Cappione JE, Lafyatis R, Dooms H,

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Arthritis & rheumatology (Hoboken, N.J.) 2017 12 15() doi 10.1002/art.40399
Abstract
OBJECTIVE
Immune dysfunction is an important component of the disease process underlying Systemic Sclerosis (SSc), but the mechanisms contributing to altered immune cell function in SSc remain poorly defined. Here, we measured the expression and function of the co-inhibitory receptors (co-IRs) PD-1, TIGIT, TIM-3, and LAG-3 in lymphocyte subsets from the peripheral blood of SSc patients.

METHODS
Co-IR expression levels on immune cell subsets were analyzed using a 16-color flow cytometry panel. The functional role of co-IRs was determined by measuring cytokine production after in vitro stimulation of PBMCs in the presence of co-IR-blocking antibodies. Supernatants from PBMC stimulation cultures were added to SSc fibroblasts and their impact on fibroblast gene expression measured. Mathematical modeling was used to reveal differences between co-IR functions in SSc patients and healthy controls.

RESULTS
The co-IRs PD-1 and TIGIT were increased, and co-expressed, in distinct T cell subsets from SSc patients, compared to healthy controls. TIM-3 was increased in SSc NK cells. PD-1, TIGIT and TIM-3 antibody blockade revealed patient-specific roles in modulating activation-induced T cell cytokine production. In contrast to healthy subjects, blocking TIGIT and TIM-3, but not PD-1, failed to reverse inhibited cytokine production in SSc patients, indicating the presence of enhanced T cell exhaustion in SSc. Finally, cytokines secreted in anti-TIM-3-treated PBMC cultures distinctly changed gene expression in SSc fibroblasts.

CONCLUSIONS
Altered expression and regulatory capacity of co-IRs in SSc lymphocytes may contribute to disease pathophysiology by modulating the cytokine-mediated crosstalk of immune cells and fibroblasts at inflammatory and/or fibrotic sites. This article is protected by copyright. All rights reserved.

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