Enhanced survival of BCG-stimulated dendritic cells: involvement of anti-apoptotic proteins and NF-κB.

Pawan Kumar,Vini John,Sangeeta Bhaskar,Ananya Gupta

doi:10.1242/bio.032045

Abstract

ABSTRACTBCG (Bacillus Calmette-Guérin) is the only available vaccine against TB and is also used for the treatment of superficial bladder cancer. BCG-mediated protection against TB and bladder cancer has been shown to rely on its ability to induce superior CD4+ and CD8+ T cell responses. As the magnitude of T cell responses is defined by dendritic cell (DC) lifespan, we examined the effect of BCG on DC survival and its underlying mechanisms. It was observed that BCG stimulation enhanced DC survival and prolonged DC lifespan in a dose-dependent manner. Live BCG led to a higher DC survival compared with heat-killed BCG. FITC-Annexin V staining showed that BCG promoted DC survival by inhibiting apoptosis. Consistently, higher expressions of anti-apoptotic proteins Bcl-2 and Bcl-xL were observed in BCG-stimulated DCs. Pharmacological inhibition of Bcl-2 and Bcl-xL drastically reduced the DC survival efficacy of BCG. Comparable survival of BCG-stimulated wild-type and MyD88−/− DCs suggested that MyD88 signaling is dispensable for BCG-induced DC survival. NF-κB is one of the key regulators of innate immune responses. We observed that pharmacological inhibition of NF-κB abrogated BCG-mediated increase in DC survival and expression of anti-apoptotic proteins. These findings provide a novel insight into the effect of BCG on DC physiology.

Highlights

BCG (Bacillus Calmette-Guérin), which was derived from Mycobacterium bovis nearly 100 years ago, is the only available vaccine against tuberculosis (TB) (Andersen and Doherty, 2005)
The intensity of T cell response is defined by dendritic cell (DC) lifespan (Kushwah and Hu, 2010)
Antigen-loaded DCs can interact with a higher proportion of cognate T cells, resulting in the heightened T cells responses

Summary

Introduction

BCG (Bacillus Calmette-Guérin), which was derived from Mycobacterium bovis nearly 100 years ago, is the only available vaccine against tuberculosis (TB) (Andersen and Doherty, 2005). BCG-mediated protection against TB relies on mounting superior Mycobacterium tuberculosis (Mtb)-specific CD4+ and CD8+ T cell responses (Kaufmann, 2006). Product Development Cell-I, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Immunotherapeutic effects of BCG vanish in athymic nude mice, underlining the central importance of T lymphocytes. Both CD4+ and CD8+ T cells mediate the immunotherapeutic efficacy of BCG as depletion of either cell type results in the failure of BCG therapy (Kawai et al, 2013)

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