ABSTRACT
In contrast to mice from the majority of inbred strains, BALB mice develop aberrant Th2 responses and suffer progressive disease after infection with Leishmania major. These outcomes depend on the production of Interleukin 4, during the first 2 d of infection, by CD4+ T cells that express the Vbeta4-Valpha8 T cell receptors specific for a dominant I-A(d) restricted epitope of the LACK antigen from L. major. In contrast to this well established role of IL-4 in Th2 cell maturation, we have recently shown that, when limited to the initial period of activation of dendritic cells by L. major preceding T cell priming, IL-4 directs DCs to produce IL-12, promotes Th1 cell maturation and resistance to L. major in otherwise susceptible BALB/c mice. Thus, the antagonistic effects that IL-4 can have on Th cell development depend upon the nature of the cells (DCs or primed T cells) targeted for IL-4 signaling.
Subject(s)
Interleukin-4/physiology , Leishmania major/immunology , Leishmaniasis, Cutaneous/immunology , Mice, Inbred BALB C/immunology , Animals , Antigens, Protozoan/immunology , Cell Differentiation , Dendritic Cells/metabolism , Genetic Predisposition to Disease , Histocompatibility Antigens Class II/immunology , Interferon-gamma/biosynthesis , Interferon-gamma/genetics , Interleukin-12/metabolism , Interleukin-4/biosynthesis , Interleukin-4/genetics , Mice , Mice, Inbred BALB C/parasitology , Mice, Transgenic , Models, Animal , RNA, Messenger/biosynthesis , Receptors, Antigen, T-Cell, alpha-beta/immunology , Th1 Cells/cytology , Th1 Cells/immunology , Th2 Cells/cytology , Th2 Cells/immunologyABSTRACT
Immunity to infection with intracellular pathogens is regulated by interleukin 12 (IL-12), which mediates protective T helper type 1 (TH1) responses, or IL-4, which induces TH2 cells and susceptibility. Paradoxically, we show here that when present during the initial activation of dendritic cells (DCs) by infectious agents, IL-4 instructed DCs to produce IL-12 and promote TH1 development. This TH1 response established resistance to Leishmania major in susceptible BALB/c mice. When present later, during the period of T cell priming, IL-4 induced TH2 differentiation and progressive leishmaniasis in resistant mice. Because immune responses developed via the consecutive activation of DCs and then T cells, the contrasting effects of IL-4 on DC development and T cell differentiation led to immune responses that had opposing functional phenotypes.
