Interleukin-23 instructs protective multifunctional CD4 T cell responses after immunization with the Mycobacterium tuberculosis subunit vaccine H1 DDA/TDB independently of interleukin-17A

Abstract

Interleukin (IL)-17A-producing T helper (Th)17 cells are increasingly being acknowledged to be associated with protective immunity to Mycobacterium tuberculosis (Mtb). Subunit vaccines potently promote protective immune responses against Mtb infection that correlate with an expansion of IL-23-dependent Th17 cells. Previous studies revealed that after vaccination, IL-23 is required for protection against challenge with Mtb but the underlying IL-23-dependent—and possibly IL-17A-mediated—mechanisms remain elusive. Therefore, we here analyzed the early outcome of Mtb infection in C57BL/6, IL-23p19-deficient (−/−), and IL-17A−/− mice after vaccination with the subunit vaccine H1-DDA/TDB to investigate the role of the IL-23-Th17 immune axis for the instruction of vaccine-induced protection. While in IL-23p19−/− mice the protective effect was reduced, protection after vaccination was maintained in IL-17A−/− animals for the course of infection of 6 weeks, indicating that after vaccination with H1-DDA/TDB early protection against Mtb is—although dependent on IL-23—not mediated by IL-17A. In contrast, IL-17A deficiency appears to have an impact on maintaining long-term protection. In fact, IL-23 instructed the vaccine-induced memory immunity in the lung, in particular the sustained expansion of tumor necrosis factor (TNF)+IL-2+ multifunctional T cells, independently of IL-17A. Altogether, a targeted induction of IL-23 during vaccination against Mtb might improve the magnitude and quality of vaccine-induced memory immune responses. Key messages After subunit Mtb vaccination with H1-DDA/TDB, IL-23 but not IL-17A contributes to vaccine-induced early protection against infection with Mtb. IL-17F does not compensate for IL-17A deficiency in terms of H1-DDA/TDB-induced protection against Mtb infection. IL 23 promotes the H1-DDA/TDB-induced accumulation of effector memory T cells independently of IL 17A. IL-23 arbitrates the induction of H1-specific IFN-γ−TNF+IL-2+ double-positive multifunctional CD4 T cells after subunit Mtb vaccination in an IL-17A-independent manner. Graphical abstract

High-Dose Mycobacterium tuberculosis H37rv Infection in IL-17A- and IL-17A/F-Deficient Mice

“…In all experiments, mice were infected with either <100 colony-forming-units (CFU), 100–1000 CFU, or >1000 CFU per lung of the lab-adapted Mtb strain H37rv using an inhalation exposure system (Glas-Col, Terre-Haute, IN, USA) as described [ 16 ]. The following day, the actual dose of infection was verified by determining CFUs in the entire lung of representative mice.…”

“…Infection with HN878 thus leads to a potent induction of IL-17A [ 7 ], suggesting that the extent of IL-17A-mediated anti-mycobacterial protection correlates with an overproduction of the cytokine. Thus, in response to certain vaccine candidates against TB, the early induction of IL-17A conveys vaccine-induced protection from Mtb challenge, but in vaccination with other candidates, the cytokine is dispensable [ 8 , 16 ]. Similarly, the increased production of IL-17A in mice with a deficiency of the specific IL-27 receptor subunit IL-27Rα mediated protection against Mtb accompanied by the formation of highly organized granulomas and an accumulation of multifunctional CD4 + T cells in the lung [ 6 , 17 ].…”

Interleukin-27 in Tuberculosis: A Sheep in Wolf’s Clothing?

“…Thus, so-called multifunctional CD4 + (Muf) T cells, which simultaneously express the cytokines IFNγ, TNF and IL-2, strongly accumulate in the lungs of Mtb-infected IL-27Rα -/- mice ( Figure 2 ). Muf T cells represent an effector T cell population with superior properties when compared to single cytokine-producing T cells ( 77 – 80 ). During Mtb infection, IFNγ and TNF appear to act synergistically to activate antimicrobial mechanisms in infected MΦ ( 79 , 81 , 82 ).…”

“…Besides, the expression of IL-2 in CD4 + T cells enhances their competitiveness for long-term survival ( 83 ). When compared to single-cytokine-producing CD4 + T cells, Muf T cells have also been demonstrated to exhibit higher cytokine production levels on the single-cell level ( 30 , 78 , 80 ). In models of vaccination against Mtb, the induction of Muf T cells correlates with antimycobacterial protection ( 78 , 80 ).…”

“…When compared to single-cytokine-producing CD4 + T cells, Muf T cells have also been demonstrated to exhibit higher cytokine production levels on the single-cell level ( 30 , 78 , 80 ). In models of vaccination against Mtb, the induction of Muf T cells correlates with antimycobacterial protection ( 78 , 80 ). Importantly, in contrast to the induction of Muf + T cells, the overall frequencies of IFNγ-producing CD4 + T cells are not influenced by the absence of IL-27Rα-mediated signalling ( 30 ).…”