Abstract
Experimental infection with the protozoan parasite Leishmania major has been extensively used to understand the mechanisms involved in T helper cell differentiation. Following infection, C57BL/6 mice develop a small self-healing cutaneous lesion and they are able to control parasite burden, a process linked to the development of T helper (Th) 1 cells. The local presence of IL-12 has been reported to be critical in driving Th1 cell differentiation. In addition, the early secretion of IL-4 was reported to potentially contribute to Th1 cell differentiation. Following infection with L. major, early keratinocyte-derived IL-4 was suggested to contribute to Th1 cell differentiation. To investigate a putative autocrine role of IL-4 signaling on keratinocytes at the site of infection, we generated C57BL/6 mice deficient for IL-4Rα expression selectively in keratinocytes. Upon infection with L. major, these mice could control their inflammatory lesion and parasite load correlating with the development of Th1 effector cells. These data demonstrate that IL-4 signaling on keratinocytes does not contribute to Th1 cell differentiation. To further investigate the source of IL-4 in the skin during the first days after L. major infection, we used C57BL/6 IL-4 reporter mice allowing the visualization of IL-4 mRNA expression and protein production. These mice were infected with L. major. During the first 3 days after infection, skin IL-4 mRNA expression was observed selectively in mast cells. However, no IL-4 protein production was detectable locally. In addition, early IL-4 blockade locally had no impact on subsequent Th1 cell differentiation and control of the disease. Taken together, the present data rule out a major role for skin IL-4 and keratinocyte IL-4Rα signaling in the development of a Th1 protective immune response following experimental infection with L. major.
Highlights
Upon infection, Leishmania protozoan parasites can cause a spectrum of diseases ranging from cutaneous, muco-cutaneous to visceral forms
To investigate the impact of IL-4Rα signaling on keratinocytes in a protective Th1 cell differentiation against cutaneous leishmaniasis, we generated mice on the C57BL/6 genetic background that are genetically deficient in IL-4Rα expression on keratinocytes (KRT14CreIL-4Rα−/lox) using the Cre/LoxP recombination system under control of the KRT14 locus
Infection did not change the frequency of cells transcribing il-4 and no IL-4 production was observed 12 and 24 h after L. major infection (Figures 5E–G). These data suggest that ear skin mast cells transcribe the il-4 gene but do not produce detectable IL-4 proteins at steady-state conditions, and L. major does not induce IL-4 production in the ear dermis early during infection. These results demonstrate that during the first hours of infection, il-4 gene expression can be detected at the infection site selectively in mast cell, but il-4 mRNA expression was not modulated during L. major infection
Summary
Leishmania protozoan parasites can cause a spectrum of diseases ranging from cutaneous, muco-cutaneous to visceral forms. Following Leishmania major experimental infection, C57BL/6 mice develop a small cutaneous lesion that is self-healing. Healing of lesion and control of parasite load were shown to result from the differentiation of CD4+ T helper (Th) 1 cells characterized by their secretion of high levels of IFNγ, a cytokine promoting the differentiation of M1 macrophages that kill intracellular parasites. Following L. major infection, BALB/c mice develop non-healing lesions and are not able to control their parasite load. This phenotype was shown to correlate with the development of CD4+ Th2 cells secreting IL-4 and IL-13 cytokines [1, 2]. The L. major experimental model was the first murine model demonstrating that the discovery of Th1 and Th2 cells subsets by Mosmann et al in vitro [4] had some relevance in vivo
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