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The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice.

ABSTRACT: CD4(+) T cells play a critical role in determining the disease outcome in murine cutaneous leishmaniasis, and selective usage of T-cell receptor (TCR) is implied in promoting Leishmania major infection. However, little information is available on TCR usage in Leishmania-specific, IFN-?-producing CD4(+) T cells. In this study, we investigated the TCR diversity and activation of CD4(+) T cells in a nonhealing model associated with L. amazonensis (La) infection and a self-healing model associated with L. braziliensis (Lb) infection. While marked expansion in the absolute number of several subsets was observed in Lb-infected mice, the percentages of TCR V?(+) CD4(+) -cell subsets were comparable in draining LN- and lesion-derived T cells in two infection models. We found that multiple TCR V? CD4(+) T cells contributed collectively and comparably to IFN-? production and that the overall levels of IFN-? production positively correlated with the control of Lb infection. Moreover, pre-infection with Lb parasites provided cross-protection against secondary La infection, owing to an enhanced magnitude of T-cell activation and IFN-? production. Collectively, this study suggests that the magnitude of CD4(+) T-cell activation, rather than the TCR diversity, is the major determining factor for the outcome of Leishmania infection.

SUBMITTER: Xin L

PROVIDER: S-EPMC4118816 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice.

Xin L L Wanderley J L JL Wang Y Y Vargas-Inchaustegui D A DA Soong L L

Parasite immunology 20110301 3

CD4(+) T cells play a critical role in determining the disease outcome in murine cutaneous leishmaniasis, and selective usage of T-cell receptor (TCR) is implied in promoting Leishmania major infection. However, little information is available on TCR usage in Leishmania-specific, IFN-γ-producing CD4(+) T cells. In this study, we investigated the TCR diversity and activation of CD4(+) T cells in a nonhealing model associated with L. amazonensis (La) infection and a self-healing model associated w ...[more]

PMID: 21306400

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Project description: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.

Dataset Information

The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice.

Publications

The magnitude of CD4(+) T-cell activation rather than TCR diversity determines the outcome of Leishmania infection in mice.

Similar Datasets

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