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Deletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection.

ABSTRACT: Effector responses induced by polarized CD4+ T helper 2 (Th2) cells drive nonhealing responses in BALB/c mice infected with Leishmania major. Th2 cytokines IL-4 and IL-13 are known susceptibility factors for L. major infection in BALB/c mice and induce their biological functions through a common receptor, the IL-4 receptor alpha chain (IL-4Ralpha). IL-4Ralpha-deficient BALB/c mice, however, remain susceptible to L. major infection, indicating that IL-4/IL-13 may induce protective responses. Therefore, the roles of polarized Th2 CD4+ T cells and IL-4/IL-13 responsiveness of non-CD4+ T cells in inducing non-healer or healer responses have yet to be elucidated. CD4+ T cell-specific IL-4Ralpha (Lck(cre)IL-4Ralpha(-/lox)) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Ralpha signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4+ T cells. Efficient deletion was confirmed by loss of IL-4Ralpha expression on CD4+ T cells and impaired IL-4-induced CD4+ T cell proliferation and Th2 differentiation. CD8+, gammadelta+, and NK-T cells expressed residual IL-4Ralpha, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Ralpha(-/lox) BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck(cre)IL-4Ralpha(-/lox) mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck(cre)IL-4Ralpha(-/lox) mice correlated with reduced numbers of IL-10-secreting cells and early IL-12p35 mRNA induction, leading to increased delayed type hypersensitivity responses, interferon-gamma production, and elevated ratios of inducible nitric oxide synthase mRNA/parasite, similar to C57BL/6 mice. These data demonstrate that abrogation of IL-4 signaling in CD4+ T cells is required to transform non-healer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Ralpha signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4+ T cells induce protective responses.

SUBMITTER: Radwanska M

PROVIDER: S-EPMC1867380 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:In BALB/c mice, susceptibility to infection with the intracellular parasite Leishmania major is driven largely by the development of T helper 2 (Th2) responses and the production of interleukin (IL)-4 and IL-13, which share a common receptor subunit, the IL-4 receptor alpha chain (IL-4Rα). While IL-4 is the main inducer of Th2 responses, paradoxically, it has been shown that exogenously administered IL-4 can promote dendritic cell (DC) IL-12 production and enhance Th1 development if given early during infection. To further investigate the relevance of biological quantities of IL-4 acting on DCs during in vivo infection, DC specific IL-4Rα deficient (CD11c(cre)IL-4Rα(-/lox)) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the cd11c locus. DNA, protein, and functional characterization showed abrogated IL-4Rα expression on dendritic cells and alveolar macrophages in CD11c(cre)IL-4Rα(-/lox) mice. Following infection with L. major, CD11c(cre)IL-4Rα(-/lox) mice became hypersusceptible to disease, presenting earlier and increased footpad swelling, necrosis and parasite burdens, upregulated Th2 cytokine responses and increased type 2 antibody production as well as impaired classical activation of macrophages. Hypersusceptibility in CD11c(cre)IL-4Rα(-/lox) mice was accompanied by a striking increase in parasite burdens in peripheral organs such as the spleen, liver, and even the brain. DCs showed increased parasite loads in CD11c(cre)IL-4Rα(-/lox) mice and reduced iNOS production. IL-4Rα-deficient DCs produced reduced IL-12 but increased IL-10 due to impaired DC instruction, with increased mRNA expression of IL-23p19 and activin A, cytokines previously implicated in promoting Th2 responses. Together, these data demonstrate that abrogation of IL-4Rα signaling on DCs is severely detrimental to the host, leading to rapid disease progression, and increased survival of parasites in infected DCs due to reduced killing effector functions.

Project description:Leishmania major (L. major) parasites are intracellular parasites belong to the Trypanosomatidae family and are the causative agent of cutaneous leishmaniasis. This disease affects approximately 1.5 million per year worldwide and there is currently no prophylactic vaccine available. L. major is transmitted by the bite of an infected sandfly and has been considered for decades now as a mouse model of choice to identify the factors implicated in T helper (Th)1 and Th2 polarization due to the natural resistance and susceptibility to infection of C57BL/6 and BALB/c mice, respectively. In this study, we refine the role of IL-12p40 cytokine, which is implicated the development of a protective Th1 response, and STAT6, a transcription factor involved in the signaling via detrimental interleukin (IL)-4 and IL-13 associated Th2 cytokines during L. major infection in the BALB/c model. In the absence of STAT6 and IL-12p40 signaling, double knockout (DKO) susceptible BALB/c mice displayed reduced footpad swelling and ulcerative lesion compared to IL-12p40-/- mice upon L. major infection. Hence, they expressed slower upregulation of keratinocyte markers implicated in the inhibition of wound healing, such as keratin 6a (Krt6a) and Krt16. This coincides with the presence of neutrophils displaying an altered phenotype characterized by a lower expression of surface markers Ly6C, CD11b, and Ly6G. These neutrophils exhibited very lower levels of apoptosis similarly to neutrophils present in resistant STAT6-/- mice. Interestingly, the reduced footpad swelling in DKO mice is associated with a high footpad parasite level similar to susceptible IL-12p40-/- mice. In conclusion, this study demonstrate that in the absence of both STAT6 and IL-12p40 signaling, L. major-infected mice display smaller and less ulcerated lesions, which does, however, not correlate with reduced parasite load. In addition, the presence of neutrophils with an altered phenotype is associated with reduced apoptosis and delayed immunopathologies, demonstrating the detrimental role of STAT6 in infected susceptible BALB/c mice.

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Deletion of IL-4Ralpha on CD4 T cells renders BALB/c mice resistant to Leishmania major infection.

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