Multidimensional analyses reveal modulation of adaptive and innate immune subsets by tuberculosis vaccines

Abstract

We characterize the breadth, function and phenotype of innate and adaptive cellular responses in a prevention of Mycobacterium tuberculosis infection trial. Responses are measured by whole blood intracellular cytokine staining at baseline and 70 days after vaccination with H4:IC31 (subunit vaccine containing Ag85B and TB10.4), Bacille Calmette-Guerin (BCG, a live attenuated vaccine) or placebo (n = ~30 per group). H4:IC31 vaccination induces Ag85B and TB10.4-specific CD4 T cells, and an unexpected NKTlike subset, that expresses IFN-γ, TNF and/or IL-2. BCG revaccination increases frequencies of CD4 T cell subsets that either express Th1 cytokines or IL-22, and modestly increases IFNγ-producing NK cells. In vitro BCG re-stimulation also triggers responses by donor-unrestricted T cells, which may contribute to host responses against mycobacteria. BCG, which demonstrated efficacy against sustained Mycobacterium tuberculosis infection, modulates multiple immune cell subsets, in particular conventional Th1 and Th22 cells, which should be investigated in discovery studies of correlates of protection.

BCG‐induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next‐generation vaccines

“…Alternative T cell-mediated resistance IFNγ independent or unconventional T cell responses might play role in the early clearance mechanism. BCG re-vaccination in humans was recently shown to boost the populations of Th1-type CD4 + T cells, expressing IFNγ, IL-2, and/or TNF, as well as CD4 + T cells expressing IL-22, highlighting the importance of unbiased analyses of vaccination responses to discover previously neglected populations 77. Th17 cells, a subset of CD4 + T cells, have been shown to confer protection against Mtb infection in murine adoptive transfer models.…”

A century of BCG: Impact on tuberculosis control and beyond

“…164 Also, BCG revaccination boosts IL-22 + CD4 + T cells in addition to Th1 cells. 186 Another trial conducted in South Africa in TST + 18-40-year-olds revealed that BCG revaccination significantly boosts pre-existing BCG-specific cytokine + (IFNγ/ IL-2/TNFα/IL-22/IL-17) CD4 + and CD8 + responses at 5 weeks postadministration. Apart from adaptive T cell responses, revaccination also boosted BCG-reactive IFNγ + NKT, NK, and γδ T cells.…”

The role of donor‐unrestricted T‐cells, innate lymphoid cells, and NK cells in anti‐mycobacterial immunity

“…Similarly, induction of NKT-like cells in humans vaccinated with the subunit vaccine candidate H4:IC31 was associated with TCR-independent, cytokine-mediated activation. 171 In the absence of IL-12/IL-18, Mtb control by murine iNKT-cells depended on CD1d and granulocyte-macrophage-colony-stimulating factor (GM-CSF). GM-CSF is associated with control of intracellular mycobacterial proliferation in vitro and with protective immunity in mice, 172,173 and was shown to be induced by Mtb antigens in in vitro human studies.…”

“…Nevertheless, the complex interactions occurring in vivo need to be addressed carefully. For instance, in addition to classical immune responses, BCG vaccination could induce trained immunity on NK cells, ILC-production of IFN-γ, and an array of DURT-mediated immune responses 62,101,171,208,214,215. The delivery route of the vaccine is an important factor to consider, since intravenous BCG vaccination of NHP induced the transient recruitment of MAIT-cells and Vγ9 + TCRγδ T-cells to the lung, and was associated with protection to Mtb challenge 62.…”