The role of IL-4 and IL-13 in cutaneous Leishmaniasis

• We update on gene-deficient mouse models of cutaneous Leishmaniasis.
• The global and cell-specific roles of IL-4 and IL-13 during disease are discussed.
• IL-4/IL-13 can drive Th2 responses or be extraneous to disease progression.
• Th2 responses can be induced independently of IL-4/IL-13.
• IL-4 can instruct protective Th1 immunity during cutaneous disease.

Murine models of Leishmania major infection in the 1980s revealed two distinct, counter-regulatory populations of CD4+ T helper (Th) cells, delineated Th1 and Th2, and their archetypal cytokines, interferon gamma (IFN-γ) and interleukin (IL)-4/IL-13, which promoted resistance/susceptibility to infection, respectively. However, the introduction of global cytokine-deficient mice in the 1990s revealed pleiotropic immune-regulatory mechanisms of IL-4 and IL-13 that either controlled or exacerbated disease. This undermined the basic premise that IL-4/IL-13 played paramount roles in facilitating a non-healing Th2 response to Leishmania infection and instead suggested that both IL-4 and IL-13-dependent and IL-4/IL-13-independent factors orchestrate disease outcome. The recent characterization of cell-type specific IL-4Rα deficient mice was initiated to help reconcile these observations and dissect the cell-specific effects of IL-4/IL-13 during infection. In this review, we summarize original and recent findings with regard to the role of IL-4 and IL-13 in cutaneous Leishmaniasis. Using the information discerned from various studies and our conditional IL-4Rα gene-deficient mice, we particularly discuss the double-edged sword IL-4 (and in some Leishmania disease models IL-13) in driving a susceptible Th2 response, their immune cell targets that support healing or non-healing responses and their novel role in mediating a Th1 response during disease.