Acute IL-4 Governs Pathogenic T Cell Responses during Leishmania major Infection

Leishmania spp. infection is a global health problem affecting more than 2 million people every year with 300 million at risk worldwide. It is well established that a dominant Th1 response (IFN-γ, a hallmark Th1 cytokine) provides resistance, whereas a dominant Th2 response (IL-4, a hallmark Th2 cytokine) confers susceptibility during infection. Given the important role of IL-4 during L. major infection, we used IL-4–neutralizing Abs to investigate the cellular and molecular events regulated by IL-4 signaling. As previously published, neutralization of IL-4 in L. major–infected BALB/c mice (a Leishmania susceptible strain) provided protection when compared with control L. major–infected BALB/c mice. Despite this protection, IFN-γ production by T cells was dramatically reduced. Temporal neutralization of IL-4 revealed that acute IL-4 produced within the first days of infection is critical for not only programming IL-4–producing Th2 CD4(+) T cells, but for promoting IFN-γ produced by CD8(+) T cells. Mechanistically, IL-4 signaling enhances anti-CD3–induced Tbet and IFN-γ expression in both CD4(+) and CD8(+) T cells. Given the pathogenic role of IFN-γ–producing CD8(+) T cells, our data suggest that IL-4 promotes cutaneous leishmaniasis pathology by not only promoting Th2 immune responses but also pathogenic CD8(+) T cell responses. Our studies open new research grounds to investigate the unsuspected role of IL-4 in regulating both Th1 and Th2 responses. ImmunoHorizons, 2020, 4: 546–560.