The increased protection and pathology in Mycobacterium tuberculosis-infected IL-27R-deficient mice is mediated by IL-17A

Einleitung: The IL-12 cytokine family member IL-27 has a broad inhibitory effect on Th1, Th2 and Th17 immune responses. With regard to Mycobacterium tuberculosis (Mtb) infection, we have previously shown that mice lacking the IL-27 receptor (IL-27R) have lower bacterial burdens in comparison to wildtype mice. However, IL-27R deficiency was associated with an accelerated death and an enhanced granulomatous response. Because IL-27R-deficient mice exhibit significantly increased numbers of IL-17A-secreting Th17 cells in their lungs, we analyzed whether the increased protection and/or pathology in the absence of IL-27R is caused by an elevated IL-17A immune response.

Methoden: We compared the outcome of Mtb-infection in IL-27R-deficient, IL-27R/IL-17A-double deficient and C57BL/6 wildtype mice.

Ergebnisse: The lower bacterial loads seen in Mtb-infected IL-27R-deficient mice, were not present in IL-27R/IL-17A-double-deficent mice during infection suggesting that protection in IL-27R-deficient mice is mediated by IL-17A. The efficient control of mycobacterial growth in IL-27R-deficient mice correlated with an enhanced presence of multifunctional T-cells, co-expressing IFN-gamma, IL-2 and TNF. This effect was mediated by IL-17A as IL-27R/IL-17A-double deficient mice exhibit similar levels of multifunctional T cells as WT mice. Eventually, IL-27R deficiency resulted in an increased body weight loss and an increased granulomatous response. However, this effect was absent in IL-27R/IL-17A-double deficient mice, indicating that the pathology in IL-27R-deficient mice was also dependent on IL-17A.

Diskussion: Taken together, IL-27 prevents optimal antimycobacterial protection as well as limits immunopathology by the inhibition of protective and damaging IL-17A immune responses. The underlying mechanisms of IL-17A-mediated protection and pathology are currently under investigation.