Epitope‐specific CD4⁺, but not CD8⁺, T‐cell responses induced by recombinant influenza A viruses protect against Mycobacterium tuberculosis infection

Abstract

Tuberculosis remains a global health problem, in part due to failure of the currently available vaccine, BCG, to protect adults against pulmonary forms of the disease. We explored the impact of pulmonary delivery of recombinant influenza A viruses (rIAVs) on the induction of Mycobacterium tuberculosis (M. tuberculosis)-specific CD4 + and CD8 + T-cell responses and the resultant protection against M. tuberculosis infection in C57BL/6 mice. Intranasal infection with rIAVs expressing a CD4 + T-cell epitope from the Ag85B protein (PR8.p25) or CD8 + T-cell epitope from the TB10.4 protein (PR8.TB10.4) generated strong T-cell responses to the M. tuberculosis-specific epitopes in the lung that persisted long after the rIAVs were cleared. Infection with PR8.p25 conferred protection against subsequent M. tuberculosis challenge in the lung, and this was associated with increased levels of poly-functional CD4 + T cells at the time of challenge. By contrast, infection with PR8.TB10.4 did not induce protection despite the presence of IFN-γ-producing M. tuberculosis-specific CD8 + T cells in the lung at the time of challenge and during infection. Therefore, the induction of pulmonary M. tuberculosis epitope-specific CD4 + , but not CD8 + T cells, is essential for protection against acute M. tuberculosis infection in the lung. Keywords: CD4 + T cells r Interferon-γ r Lung r Recombinant influenza A virus r TuberculosisAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionTuberculosis (TB) is still one of the major causes of death worldwide, and it is estimated that one-third of the world's population Correspondence: Dr. Manuela Flórido e-mail: m.florido@centenary.org.au is infected by Mycobacterium tuberculosis (M. tuberculosis; WHO 2012, http://www.who.int/tb/publications/global_report). The only vaccine currently used, BCG, although effective at protecting young children, fails to protect adults from the pulmonary form of the disease with efficacies that range from 0 to 80% [1]. The most advanced vaccine in human studies is MVA85A, a nonreplicative vaccinia viral vector expressing M. tuberculosis Ag85A, but the results of a phase II clinical trial showed no additional C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 780-793 Immunity to infection 781 protective effect of this vaccine over BCG against clinical TB or the acquisition of M. tuberculosis infection in infants [2]. The development of more effective vaccines is therefore essential. The immune response against primary infection with M. tuberculosis in a naïve host involves mostly CD4 + T cells so unsurprisingly anti-TB vaccines were initially designed to induce a strong CD4 + T-cell response. That was the case for BCG and subunit vaccines that are potent inducers of systemic anti-M. tuberculosis CD4 + T-cell responses [3]. Emerging evidence that CD8 + T cells also played a role in both the immune response to M. tuberculosis infection and in the vaccin...

The generation of T‐cell memory to protect against tuberculosis

“…In mice, BCG is a poor stimulator of CD8 + T‐cell responses compared with M. tuberculosis and this is the rationale for the development of vaccines targeting CD8 + T‐cell expansion . However, viral and subunit vaccines that lead to strong CD8 + T‐cell responses in mice did not improve protection against M. tuberculosis infection . Both these studies, however, used the immunodominant M. tuberculosis antigen, TB10.4, and TB10.4‐specific CD8 + T cells appear unable to recognize M. tuberculosis ‐infected macrophages, which suggests that M. tuberculosis may subvert the CD8 + T‐cell responses as a virulence strategy.…”

“…38 However, viral and subunit vaccines that lead to strong CD8 + T-cell responses in mice did not improve protection against M. tuberculosis infection. 39,40 Both these studies, however, used the immunodominant M. tuberculosis antigen, TB10.4, and TB10.4-specific CD8 + T cells appear unable to recognize M. tuberculosisinfected macrophages, 41 which suggests that M. tuberculosis may subvert the CD8 + T-cell responses as a virulence strategy. Despite this, a number of TB vaccines in clinical trials are designed to elicit a strong CD8 + T-cell response ( Table 1).…”

Pulmonary immunization with a recombinant influenza A virus vaccine induces lung-resident CD4+ memory T cells that are associated with protection against tuberculosis

“…[17][18][19] We have previously shown that pulmonary immunization of mice with a viral TB vaccine, recombinant influenza A virus (rIAV) expressing the p25 CD4 + T-cell immunodominant epitope of M. tuberculosis Ag85B (PR8.p25), induced strong p25-specific CD4 + Tcell responses in the lungs that were protective against M. tuberculosis challenge. 20 In this study, we have investigated whether pulmonary immunization of mice with rIAVs expressing this p25 epitope induces M. tuberculosis-specific CD4 + T cells in the lung with the tissue location, phenotype, and transcriptional characteristics of T RMs , and if these lung-resident T cells are protective against M. tuberculosis challenge in the absence of circulating memory T cells.…”

TB vaccines; promoting rapid and durable protection in the lung

“…CD8 T cell responses increase later during infection often with a kinetic that is associated with increasing bacterial burden. Their role in protective immunity remain unresolved and recent data suggest that even very high numbers of vaccine promoted CD8 T cells specific for protective antigens fail to influence Mtb growth [20, 21]. …”