Targeting dendritic cells to accelerate T-cell activation overcomes a bottleneck in tuberculosis vaccine efficacy

Kristin L. Griffiths, Mushtaq Ahmed, Shibali Das, Radha Gopal, William Horne, Terry D. Connell, Kelly D. Moynihan, Jay K. Kolls, Darrell J. Irvine, Maxim N. Artyomov, Javier Rangel-Moreno and Shabaana A. Khader ()
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Kristin L. Griffiths: Washington University in St Louis
Mushtaq Ahmed: Washington University in St Louis
Shibali Das: Washington University in St Louis
Radha Gopal: Richard King Mellon Foundation Institute for Pediatric Research, Children’s Hospital of Pittsburgh of UPMC
William Horne: Richard King Mellon Foundation Institute for Pediatric Research, Children’s Hospital of Pittsburgh of UPMC
Terry D. Connell: Witebsky Center for Microbial Pathogenesis & Immunology, University at Buffalo
Kelly D. Moynihan: Massachusetts Institute of Technology
Jay K. Kolls: Richard King Mellon Foundation Institute for Pediatric Research, Children’s Hospital of Pittsburgh of UPMC
Darrell J. Irvine: Massachusetts Institute of Technology
Maxim N. Artyomov: Washington University in St Louis
Javier Rangel-Moreno: Immunology and Rheumatology, University of Rochester Medical Center
Shabaana A. Khader: Washington University in St Louis

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract The development of a tuberculosis (TB) vaccine that induces sterilizing immunity to Mycobacterium tuberculosis infection has been elusive. Absence of sterilizing immunity induced by TB vaccines may be due to delayed activation of mucosal dendritic cells (DCs), and subsequent delay in antigen presentation and activation of vaccine-induced CD4+ T-cell responses. Here we show that pulmonary delivery of activated M. tuberculosis antigen-primed DCs into vaccinated mice, at the time of M. tuberculosis exposure, can overcome the delay in accumulation of vaccine-induced CD4+ T-cell responses. In addition, activating endogenous host CD103+ DCs and the CD40–CD40L pathway can similarly induce rapid accumulation of vaccine-induced lung CD4+ T-cell responses and limit early M. tuberculosis growth. Thus, our study provides proof of concept that targeting mucosal DCs can accelerate vaccine-induced T-cell responses on M. tuberculosis infection, and provide insights to overcome bottlenecks in TB vaccine efficacy.

Date: 2016
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DOI: 10.1038/ncomms13894

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