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Author Notes:

Corresponding author: Suraj B. Sable: ssable@cdc.gov

The preclinical BCG vaccine and Mtb Erdman challenge standards were provided by Amy Yang, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD.

The findings and conclusions in this publication are those of the authors and do not necessarily represent the official position of CDC, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The authors confirm that all data underlying the findings are fully available without restriction.

All relevant data are within the paper and its Supporting Information files.

For a full list of contributions, please refer to the full article.

Conceived and designed the experiments: SN SK SBS.

Performed the experiments: SN SK SBS.

Analyzed the data: SN SK SBS. Contributed reagents/materials/analysis tools: JEP RRA.

Contributed to the writing of the manuscript: SN JEP SBS.

The authors have declared that no competing interests exist.

Subjects:

Research Funding:

The study was supported by Centers for Disease Control and Prevention (CDC) intramural funds and the Georgia Research Alliance grant to SBS, RRA, JEP, and TM Shinnick.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MYCOBACTERIUM-BOVIS BCG
  • BACILLUS-CALMETTE-GUERIN
  • CHRONIC VIRAL-INFECTION
  • INTERFERON-GAMMA
  • IMMUNE-RESPONSE
  • CENTRAL MEMORY
  • ANTIGEN LOAD
  • PULMONARY TUBERCULOSIS
  • PUBLISHED LITERATURE
  • EFFECTOR FUNCTIONS

Attrition of T-Cell Functions and Simultaneous Upregulation of Inhibitory Markers Correspond with the Waning of BCG-Induced Protection against Tuberculosis in Mice

Journal Title:

PLoS ONE

Volume:

Volume 9, Number 11

Publisher:

, Pages e113951-e113951

Type of Work:

Article | Final Publisher PDF

Abstract:

Mycobacterium bovis bacille Calmette-Guérin (BCG) is the most widely used live attenuated vaccine. However, the correlates of protection and waning of its immunity against tuberculosis is poorly understood. In this study, we correlated the longitudinal changes in the magnitude and functional quality of CD4(+) and CD8(+) T-cell response over a period of two years after mucosal or parenteral BCG vaccination with the strength of protection against Mycobacterium tuberculosis in mice. The BCG vaccination-induced CD4(+) and CD8(+) T cells exhibited comparable response kinetics but distinct functional attributes in-terms of IFN-γ, IL-2 and TNF-α co-production and CD62L memory marker expression. Despite a near life-long BCG persistence and the induction of enduring CD4(+) T-cell responses characterized by IFN-γ and/or TNF-α production with comparable protection, the protective efficacy waned regardless of the route of vaccination. The progressive decline in the multifactorial functional abilities of CD4(+) and CD8(+) T cells in-terms of type-1 cytokine production, proliferation and cytolytic potential corresponded with the waning of protection against M. tuberculosis infection. In addition, simultaneous increase in the dysfunctional and terminally-differentiated T cells expressing CTLA-4, KLRG-1 and IL-10 during the contraction phase of BCG-induced response coincided with the loss of protection. Our results question the empirical development of BCG-booster vaccines and emphasize the pursuit of strategies that maintain superior T-cell functional capacity. Furthermore, our results underscore the importance of understanding the comprehensive functional dynamics of antigen-specific T-cell responses in addition to cytokine polyfunctionality in BCG-vaccinated hosts while optimizing novel vaccination strategies against tuberculosis.

Copyright information:

This is an Open Access work distributed under the terms of the Creative Commons Universal : Public Domain Dedication License (http://creativecommons.org/publicdomain/zero/1.0/).

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