Experimental infection with the protozoan parasite has been extensively used to understand the mechanisms involved in T helper cell differentiation. cutaneous, muco-cutaneous to visceral forms. Following 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 IFN, a cytokine promoting the differentiation of M1 macrophages that kill intracellular parasites. In contrast, following 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). These cytokines induce the differentiation of M2 macrophages that favor parasite survival within macrophages (3). The experimental model was the first murine model demonstrating that the discovery of Th1 and Th2 cells subsets by Mosmann et al. (4) had some Ertapenem sodium relevance (5). In contrast the role of IL-4 in susceptibility and Th2 cell differentiation is more controversial. Following infection with (LV39), IL-4?/? or IL-4R?/? mice on a BALB/c genetic background were able to control lesion size and the levels of IFN present in draining lymph node (dLN) cells was either very low or remained unchanged compared to that observed in BALB/c wild-type mice (6, 7). These data suggested that IL-4 was critical for susceptibility and Th2 cell differentiation. The C57Bl/6×129 IL-4?/? mice used in these scholarly studies were backcrossed for six generations onto the BALB/c genetic background. In contrast, pursuing disease with LV39 IL-4?/? mice produced with embryonic stem cells of BALB/c source still developed intensifying non-healing lesions which were much like those of likewise contaminated wild-type BALB/c mice (8). Disease of the mice with another stress of (IR173) led to incomplete control of lesion size in IL-4?/? mice, Ertapenem sodium while IL-4R?/? managed lesion size effectively (9). Additional research using IL-4 or IL-4R-deficient mice demonstrated that following disease with Th2 differentiation could develop Ertapenem sodium in lack of IL-4 (10C12). Particular deletion of IL-4R signaling on T cells led to a curing phenotype in BALB/c mice connected with improved IFN response, recommending a job for IL-4 and IL-13 in susceptibility pursuing disease (13). Collectively, these total outcomes indicated that along with IL-4, IL-13, and additional factors are involved in the control of Th2 cell differentiation and susceptibility (14). In addition, several lines of evidence suggest that IL-4 may be needed for Rtn4r Th1?cell differentiation. Unlike what was observed following infection, IL-4-deficient mice failed to develop Th1?cells in response to infection with (15) suggesting a potential role for endogenous IL-4 in Th1?cell differentiation and protective antifungal response. Furthermore, local injection of exogenous recombinant IL-4 within the first 8?h of infection in BALB/c mice was sufficient to Ertapenem sodium modify the development of the immune response from an otherwise Th2 immune response into a Ertapenem sodium protective type-1 Th1 response (16). It was hypothesized that IL-4, by acting on dendritic cells, induced their IL-12 secretion (16), a process that had previously been reported on macrophages and DCs (17C19). In addition, dendritic cell-specific IL-4R-deficient mice on the BALB/c genetic background developed larger lesions and increased Th2 response, suggesting some protective role for endogenous IL-4 acting on DCs during LV39 and IL-81 infection (20). Collectively, these studies suggested that within the first hours of infection the transient presence of IL-4 could contribute to the differentiation of CD4+ Th1?cells. In this line, skin keratinocytes present in the footpad of mice infected with subcutaneously were identified as an early IL-4 source contributing to the launching of CD4+ Th1?cell differentiation (21). Interestingly, in that study, IL-4 transcription appeared restricted to keratinocytes from C57BL/6 mice and only low IL-4 mRNA levels were observed in BALB/c keratinocytes. Moreover, in the same study, the upregulation of IL-4 mRNA observed in C57BL/6 keratinocytes was shown to be restricted to a very small time window at the onset of infection. Finally, impaired Th1?cell development was observed in C57BL/6 mice following blocking of IL-4 protein with an anti-IL-4 mAb at the cutaneous infection site (21). Targeting IL-4 at the infection site could be of potential interest in the design of vaccines. Here, we investigated the role of skin IL-4R signaling, more specifically the contribution of keratinocyte-derived IL-4R signaling during the first days of infection and its subsequent impact on the development of a protective type-1 immune response in C57BL/6 mice. To this end, we generated C57BL/6 mice.
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