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

Abstract

In tuberculosis (TB), protective inflammatory immune responses and the pathological sequelae of chronic inflammation significantly depend on a timely balance of cytokine expression. In contrast to other anti-inflammatory cytokines, interleukin (IL)-27 has fundamental effects in experimental Mycobacterium tuberculosis (Mtb) infection: the absence of IL-27-mediated signalling promotes a better control of mycobacterial growth on the one hand side but also leads to a chronic hyperinflammation and immunopathology later during infection. Hence, in the context of novel host-directed therapeutic approaches and vaccination strategies for the management of TB, the timely restricted blockade of IL-27 signalling may represent an advanced treatment option. In contrast, administration of IL-27 itself may allow to treat the immunopathological consequences of chronic TB. In both cases, a better knowledge of the cell type-specific and kinetic effects of IL-27 after Mtb infection is essential. This review summarizes IL-27-mediated mechanisms affecting protection and immunopathology in TB and discusses possible therapeutic applications.

Ablation of B cell-derived IL-10 increases tuberculosis resistance

“…Male control mice exhibited significantly lower IFN-γ but higher IL-27 levels compared to females. IFN-γ is essential to control TB infection [29,30], whereas IL-27 has been previously shown to exhibit a double-edged sword effect: suppressing protective immunity against TB and bacterial clearance, while simultaneously dampening excessive inflammation [28,31,32]. Studies using mice deficient in WSX-1, a component of the IL-27 receptor, revealed increased activation of CD4 + T cells and IFN-γ production [32].…”

“…IL-27, like IL-10, is an important anti-inflammatory cytokine that has a dual role in TB. On the one hand, IL-27 limits protective immunity to Mtb but on the other hand it prevents from excessive inflammation and immunopathology [28]. Thus, we next evaluated the granulomatous response in absence of B cellderived IL-10, which led to a significant reduction in IL-27 levels in males (see Fig.…”

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

“…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 ].…”