Transmembrane Tumor Necrosis Factor Controls Myeloid-Derived Suppressor Cell Activity via TNF Receptor 2 and Protects from Excessive Inflammation during BCG-Induced Pleurisy.

Leslie Chavez-Galan,Mahdia Benkhoucha,Irene Garcia,Husnu Uysal,Dominique Vesin,Guillaume Blaser,Bernhard Ryffel,Valérie F. J. Quesniaux

doi:10.3389/fimmu.2017.00999

Abstract

Pleural tuberculosis (TB) is a form of extra-pulmonary TB observed in patients infected with Mycobacterium tuberculosis. Accumulation of myeloid-derived suppressor cells (MDSC) has been observed in animal models of TB and in human patients but their role remains to be fully elucidated. In this study, we analyzed the role of transmembrane TNF (tmTNF) in the accumulation and function of MDSC in the pleural cavity during an acute mycobacterial infection. Mycobacterium bovis BCG-induced pleurisy was resolved in mice expressing tmTNF, but lethal in the absence of tumor necrosis factor. Pleural infection induced MDSC accumulation in the pleural cavity and functional MDSC required tmTNF to suppress T cells as did pleural wild-type MDSC. Interaction of MDSC expressing tmTNF with CD4 T cells bearing TNF receptor 2 (TNFR2), but not TNFR1, was required for MDSC suppressive activity on CD4 T cells. Expression of tmTNF attenuated Th1 cell-mediated inflammatory responses generated by the acute pleural mycobacterial infection in association with effective MDSC expressing tmTNF and interacting with CD4 T cells expressing TNFR2. In conclusion, this study provides new insights into the crucial role played by the tmTNF/TNFR2 pathway in MDSC suppressive activity required during acute pleural infection to attenuate excessive inflammation generated by the infection.

Highlights

Tuberculosis (TB) is an infectious disease that remains a major health problem worldwide causing high morbidity and mortality
To further evaluate whether transmembrane TNF or soluble-TNF form is required for protection during pleural mycobacterial infection, we analyzed mice that express a mutated form of TNF that cannot be cleaved by TACE and do not produce solTNF [29]
We find that proliferation of activated CD4 T cells deprived of TNF receptor 2 (TNFR2) were not inhibited by MDSC, suggesting that the interaction of transmembrane TNF (tmTNF) expressed by MDSC and TNFR2 on CD4 T cells is critical for MDSC-mediated T cell suppression

Summary

Introduction

Tuberculosis (TB) is an infectious disease that remains a major health problem worldwide causing high morbidity and mortality. The pulmonary form is the most common form of TB infection but extra-pulmonary TB accounts for about one-third of reported TB cases [1]. Pleural TB is considered as a form of extra-pulmonary TB which is a frequent clinical problem consisting in the accumulation of fluid and pleural cells in the pleural cavity subsequent to Mycobacterium tuberculosis infection [3, 4]. Pleural TB has been reported as a primary TB pleurisy consequent to the rupture of pulmonary subpleural caseous lesions into the pleural space [5]. Pleural TB can be observed in patients with reactivation of latent TB and, in certain cases, associated with the use of corticosteroid and anti-TNF treatments or presence of comorbidities as HIV/AIDS and diabetes [6]

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