Deletion of IL-4Rα on CD4 T Cells Renders BALB/c Mice Resistant to Leishmania major Infection (original) (raw)
Effector responses induced by polarized CD4 þ 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 a chain (IL-4Ra). IL-4Radeficient 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 þ T cells and IL-4/IL-13 responsiveness of non-CD4 þ T cells in inducing nonhealer or healer responses have yet to be elucidated. CD4 þ T cell-specific IL-4Ra (Lck cre IL-4Ra À/lox ) deficient BALB/c mice were generated and characterized to elucidate the importance of IL-4Ra signaling during cutaneous leishmaniasis in the absence of IL-4-responsive CD4 þ T cells. Efficient deletion was confirmed by loss of IL-4Ra expression on CD4 þ T cells and impaired IL-4-induced CD4 þ T cell proliferation and Th2 differentiation. CD8 þ , cd þ , and NK-T cells expressed residual IL-4Ra, and representative non-T cell populations maintained IL-4/IL-13 responsiveness. In contrast to IL-4Ra À/lox BALB/c mice, which developed ulcerating lesions following infection with L. major, Lck cre IL-4Ra À/lox mice were resistant and showed protection to rechallenge, similar to healer C57BL/6 mice. Resistance to L. major in Lck cre IL-4Ra À/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-c 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 þ T cells is required to transform nonhealer BALB/c mice to a healer phenotype. Furthermore, a beneficial role for IL-4Ra signaling in L. major infection is revealed in which IL-4/IL-13-responsive non-CD4 þ T cells induce protective responses.
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2015
B-lymphocytes are considered to play a minimal role in host defense against Leishmania major. 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). To investigate the relevance IL-4Rα mediated signalling in B Lymphocytes independently of non-B cells during the early stage in vivo infection, B-lymphocytes specific IL-4Rα deficient (MB-1-hCreIL4Rα -/LOX ) BALB/c mice were generated by gene targeting and site-specific recombination using the cre/loxP system under control of the MB-1 locus. DNA functional characterization through RT-PCR showed a balanced IL-4Rα expression on B-lymphocytes in MB-1-hCre IL4Rα -/LOX mice. We conclude from these data that the balanced expression shows that the Th differentiation doesn’t happen in the early stage of infection...
Journal of immunology (Baltimore, Md. : 1950), 1997
IL-4 drives polarized Th2 responses, and differentiating Th2 cells down-regulate their sensitivity to IL-12. Therefore, the failure of BALB/c mice to heal Leishmania major infection could be due to an IL-4-dependent biased Th2 response or to a reduced capacity of Leishmania-specific Th cells to respond to IL-12. We examined the ability of CD4+ Th cells from L. major-infected wild-type and IL-4-deficient BALB/c mice to respond to IL-12. We show that the inability of normal and IL-4-deficient BALB/c mice to heal L. major infections is due to their inability to generate effective Th1 responses and not to persistent IL-4-dominated Th2 responses. Redirection of immune responses in vivo by administration of IL-12 or anti-CD4 mAb treatment in the early phase of infection (+/-12 days) allows both normal and IL-4-deficient BALB/c mice to heal their lesions by allowing them to develop an efficient Th1 response regardless of the presence or the absence of IL-4. Finally, on a population level, ...
IL-4-deficient Balb/c mice resist infection with Leishmania major
The Journal of experimental medicine, 1996
Mice with a genetically engineered deficiency for either IL-4 or IFN-gamma R1 (single mutants), and IL-4/IFN-gamma R1 (double mutants) on the Balb/c and 129Sv background were used to study the course of infection with Leishmania major. In contrast to genetically resistant 129Sv wildtype mice, IL-4/IFN-gamma R1 double mutant mice developed fetal disease with parasite dissemination to visceral organs similar to mice lacking IFN-gamma R1 only. Balb/c mice, which are exquisitely susceptible to L. major, were rendered resistant to infection by disruption of the IL-4 gene. As compared to homozygous IL-4+/- mice, heterozygous IL-4+/- mice, heterozygous IL-4+/- animals consistently developed smaller lesions with less ulceration and necrosis, indicating the likelihood of gene-dosage effects. This implicates that the magnitude of the IL-4 response determines the severity of disease. CD4+ T cells of IL-4-deficient mice showed impaired Th2 cell development, as assessed by quantitative RT-PCR of...
Early IL-4 Production Does Not Predict Susceptibility toLeishmania major
Experimental Parasitology, 1996
mania major in mice can be self-limiting or fatal, depending upon the inbred mouse strain. It is well established that the outcome of infection is dependent upon the Th cell subset that dominates after infection. This has led to intense study of the early events associated with infection, in order to better understand the factors that determine Th1/2 cell development. In the present report, we have analyzed the kinetics of IL-4 and IL-4 mRNA production in three mouse strains: BALB/c, C3H, and C57BL/6. We found that in the first week IL-4 is absent in the C3H mice, but present in the susceptible BALB/c and relatively resistant C57BL/6 mouse. These data indicate that the presence of IL-4 by itself does not determine whether the immune response will be dominated by Th2 cells, since C57BL/6 mice will eventually develop a Th1 response and heal. We suggest that the critical cytokine that determines susceptibility in experimental leishmaniasis is IL-12, rather than IL-4. Thus, in C3H mice IL-12 is evident soon after infection, and IL-4 responses are not observed. In C57BL/6 mice, IL-12 production is delayed, but once evident, the IL-4 response is ablated. Further, we show that addition of IL-12 can block early IL-4 production in BALB/c mice, and neutralization of IL-12 in C3H mice uncovers IL-4 production in response to L. major infection. Taken together, these data indicate that susceptibility to L. major, while possibly requiring IL-4, is not determined by the presence or absence of IL-4.
The Journal of Immunology, 2002
Leishmania major result from early IL-4 production by V4V␣8 CD4 ؉ T cells in response to the Leishmania homolog of mammalian RACK1 Ag. A role for CD4 ؉ CD25 ؉ regulatory T cells in the control of this early IL-4 production was investigated by depleting in vivo this regulatory T cell population. Depletion induced an increase in the early burst of IL-4 mRNA in the draining lymph nodes of BALB/c mice, and exacerbated the course of disease with higher levels of IL-4 mRNA and protein in their lymph nodes. We further showed that transfer of 10 7 BALB/c spleen cells that were depleted of CD4 ؉ CD25 ؉ regulatory T cells rendered SCID mice susceptible to infection and allowed Th2 differentiation while SCID mice reconstituted with 10 7 control BALB/c spleen cells were resistant to infection with L. major and developed a Th1 response. Treatment with a mAb against IL-4 upon infection with L. major in SCID mice reconstituted with CD25-depleted spleen cells prevented the development of Th2 polarization and rendered them resistant to infection. These results demonstrate that CD4 ؉ CD25 ؉ regulatory T cells play a role in regulating the early IL-4 mRNA and the subsequent development of a Th2 response in this model of infection.
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