Tuberculosis

CD137 differentially regulates innate and adaptive immunity against Mycobacterium tuberculosis.

Darío A. Fernández Do Porto*, Javier O. Jurado*, Virginia Pasquinelli*, Ivana B. Alvarez*, Romina H. Aspera*, Rosa M. Musella†, and Verónica E. García*

*Department of Biological Chemistry, University of Buenos Aires, School of Sciences, Buenos Aires, Argentina.
† División de Tisioneumonología,Hospital F.J. Muñiz, Buenos Aires, Argentina.

Address correspondence to:
Verónica E. García, Ph.D.
Independent Researcher
National Council of Science and Technology (CONICET)
Department of Biological Chemistry,
University of Buenos Aires, School of Sciences,
Intendente Güiraldes 2160, 1428, Capital Federal,
Buenos Aires, Argentina.
Telephone/Fax: (54) 11 4576-3342
Email:vgarcia@qb.fcen.uba.ar

Running title: Role of CD137 in tuberculosis

Abstract

Protective immunity against Mycobacterium tuberculosis is primarily mediated by the interaction of antigen-specific T cells and APC, which often depends on the interplay of cytokines produced by these cells. Costimulatory signals represent a complex network of receptor-ligand interactions that qualitatively andquantitatively influence immune responses. Thus, here we investigated the function of CD137 and CD137L, molecules known to play a central role in immune regulation, during human tuberculosis. We demonstrated that specific antigen-stimulation increased both CD137 and CD137L expression on monocytes and NK cells from tuberculosis patients and healthy donors, but only up-regulated CD137 on T lymphocytes.Blockage of the CD137 pathway enhanced the levels of IFN-γ and TNF-α produced by monocytes and NK against M. tuberculosis. In contrast, CD137 blockage significantly decreased the specific degranulation of CD8+ T cells and the percentage of specific IFN-γ and TNF-α producing lymphocytes against the pathogen. Furthermore, inhibition of the CD137 pathway markedly increased T cell apoptosis. Takentogether, our results demonstrate that CD137:CD137L interactions regulate the innate and adaptive immune response of the host against M. tuberculosis.

Keywords: CD137, Cytokines, monocytes, NK cells, T cells, Tuberculosis
Introduction

Tuberculosis remains an enormous global health problem despite current drug treatment. The disease causes nearly 9 million new cases and 1.7 million deathsannually worldwide, and is among the most common causes of morbidity and mortality in patients with HIV infection. Bacillus Calmette-Guérin, the only available vaccine, is of variable efficacy, especially in tuberculosis-endemic regions, such as Argentina. Development of a more effective vaccine depends on a better understanding of the human immune response to this pathogen. Although protectiveimmunological mechanisms against M. tuberculosis are not fully understood, resistance to mycobacterial infections is primarily mediated by the interaction of antigen-specific T cells and macrophages [pic]1, 2. This interaction is often dependent on the interplay of cytokines produced by these cells. Even though a broad spectrum of cytokines may contribute to protection, a type 1 response, dominated byIFN-γ secretion, is considered a principal mediator of protective immunity against M. tuberculosis [pic]2, 3. Besides, CD8+ T lymphocytes also contribute to protection by lysing infected cells [pic]4. In addition, innate immune response-related pro-inflammatory cytokines, IL-6, IL-12, TNF-α, initiate events that limit mycobacterial growth by recruiting monocytes into the lesions and activatingthem 5. In particular, TNF-α, mainly secreted by activated macrophages, contributes to anti-tubercular action and limits disease pathology 1. Therefore, it is considered of vast interest to investigate the regulation of cytokine responses during active tuberculosis.
Several signaling proteins contribute to the active up- or down-regulation during the priming of a T cell [pic]6, modulating...