Control of Leishmania major in the absence of Tyk2 kinase

IL-12 is indispensable for the control of many intracellular pathogens, but the components of the signaling pathway that are essential for its function in vivo are incompletely understood. Here, we investigated in the Leishmania major mouse model whether Tyk2 kinase is required for the generation of a protective immune response. Unlike C57BL/6 controls, Tyk2(-/-) mice developed severe skin lesions after infection that frequently ulcerated, but ultimately healed. NK cell cytotoxicity was absent in infected Tyk2(-/-) mice, even after IL-12 pretreatment, which correlated with a STAT4 activation defect. IFN-alpha/beta, which was still able to activate STAT1 in Tyk2(-/-) NK cells, reconstituted their cytotoxic activity, but not their IL-12 responsiveness. The IL-12-induced production of IFN-gamma by NK cells and CD8(+) T cells was strongly suppressed in Tyk2(-/-) mice at day 1 of infection, but partly regained during the late phase of infection. Tyk2(-/-) CD4(+) T cells developed into Th1 cells (although in a delayed fashion) and infected Tyk2(-/-) mice expressed normals levels of inducible NO synthase. Thus, Tyk2 is required for the IL-12 response of NK cells and CD8(+) T cells in L. major-infected mice, but not for the generation of Th1 cells and the ultimate control of the disease.