sq-23377 and Leishmaniasis--Cutaneous

Activated CD4(+) T helper cells (Th) comprise at least two functionally distinct subsets, Th1 and Th2, which mediate different immunological effector functions. Experimental leishmaniasis is widely used to study the effector function of Th cell subsets in vivo. Healing and nonhealing Leishmania major infections have been correlated with polarized Th1 and Th2 responses, respectively. In the study presented here, a stable cell surface marker expressed on Th2 cells, T1/ST2, has been used to assess the distribution of CD4(+) T1/ST2(+) T cells in different organs of healer and nonhealer strains of mice during the course of L. major infection. The frequency of CD4(+) T cells expressing the T1/ST2 cell surface marker and Th2 cytokines in the lymphoid organs was low in both strains of infected mice; however, CD4(+) T1/ST2(+) T cells could be enriched from the lymphoid organs of infected nonhealer but not from healer strains of mice. The highest frequency of CD4(+) T1/ST2(+) T cells was detected in the footpads of mice with nonhealing disease, showing that CD4(+) T1/ST2(+) T cells home to the footpads. Since the majority of parasites persist at the local site of infection in nonhealing BALB/c mice, these results show that CD4(+) T1/ST2(+) T cells are localized at the site of active infection and inflammation in this model.

Topics: Animals; CD5 Antigens; Cell Differentiation; Chronic Disease; Disease Susceptibility; Female; Interleukin-1 Receptor-Like 1 Protein; Ionomycin; Leishmania major; Leishmaniasis, Cutaneous; Lymph Nodes; Lymphocyte Activation; Lymphoid Tissue; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred CBA; Organ Specificity; Phenotype; Receptors, Interleukin; Schistosomiasis mansoni; Specific Pathogen-Free Organisms; Spleen; T-Lymphocyte Subsets; Tetradecanoylphorbol Acetate; Th2 Cells

Naive Itk-deficient CD4+ T cells were unable to establish stable IL-4 production, even when primed in Th2-inducing conditions. In contrast, IFNgamma production was little affected. Failure to express IL-4 occurred even among cells that had gone through multiple cell divisions and was associated with a delay in the kinetics and magnitude of NFATc nuclear localization. IL-4 production was restored genetically by retroviral reconstitution of Itk or biochemically by augmenting the calcium flux with ionomycin. In vivo, Itk-deficient mice were unable to establish functional Th2 cells. Development of protective Th1 cells was unimpeded. These data define a nonredundant role for Itk in modulating signals from the TCR/CD28 pathways that are specific for the establishment of stable IL-4 but not IFNgamma expression.

Topics: Animals; Biological Transport; Calcium Signaling; CD28 Antigens; Cell Differentiation; Cell Division; Disease Progression; DNA-Binding Proteins; Female; Gene Expression Regulation; Interferon-gamma; Interleukin-2; Interleukin-4; Ionomycin; Ionophores; Leishmania major; Leishmaniasis, Cutaneous; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NFATC Transcription Factors; Nuclear Proteins; Protein-Tyrosine Kinases; Receptors, Antigen, T-Cell; Recombinant Fusion Proteins; Specific Pathogen-Free Organisms; Th2 Cells; Transcription Factors