ABSTRACT
Th2 memory lymphocytes have imprinted their Il4 genes epigenetically for expression in dependence of T cell receptor restimulation. However, in a given restimulation, not all Th cells with a memory for IL-4 expression express IL-4. Here, we show that in reactivated Th2 cells, the transcription factors NFATc2, NF-kB p65, c-Maf, p300, Brg1, STAT6, and GATA-3 assemble at the Il4 promoter in Th2 cells expressing IL-4 but not in Th2 cells not expressing it. NFATc2 is critical for assembly of this transcription factor complex. Because NFATc2 translocation into the nucleus occurs in an all-or-none fashion, dependent on complete dephosphorylation by calcineurin, NFATc2 controls the frequencies of cells reexpressing Il4, translates analog differences in T cell receptor stimulation into a digital decision for Il4 reexpression, and instructs all reexpressing cells to express the same amount of IL-4. This analog-to-digital conversion may be critical for the immune system to respond to low concentrations of antigens.
Subject(s)
Cell Nucleus/metabolism , Gene Expression Regulation/physiology , Interleukin-4/biosynthesis , NFATC Transcription Factors/metabolism , Response Elements/physiology , Th2 Cells/metabolism , Active Transport, Cell Nucleus/physiology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/immunology , Adaptor Proteins, Signal Transducing/metabolism , Animals , Cell Nucleus/genetics , Cell Nucleus/immunology , DNA Helicases/genetics , DNA Helicases/immunology , DNA Helicases/metabolism , E1A-Associated p300 Protein/genetics , E1A-Associated p300 Protein/immunology , E1A-Associated p300 Protein/metabolism , GATA3 Transcription Factor/genetics , GATA3 Transcription Factor/immunology , GATA3 Transcription Factor/metabolism , Interleukin-4/genetics , Interleukin-4/immunology , Mice , Mice, Inbred BALB C , Mice, Transgenic , NFATC Transcription Factors/genetics , NFATC Transcription Factors/immunology , Nuclear Proteins/genetics , Nuclear Proteins/immunology , Nuclear Proteins/metabolism , Phosphorylation/physiology , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , STAT6 Transcription Factor/genetics , STAT6 Transcription Factor/immunology , STAT6 Transcription Factor/metabolism , Th2 Cells/cytology , Th2 Cells/immunology , Transcription Factor RelA/genetics , Transcription Factor RelA/immunology , Transcription Factor RelA/metabolism , Transcription Factors/genetics , Transcription Factors/immunology , Transcription Factors/metabolismABSTRACT
After being activated by antigen, helper T lymphocytes switch from a resting state to clonal expansion. This switch requires inactivation of the transcription factor Foxo1, a suppressor of proliferation expressed in resting helper T lymphocytes. In the early antigen-dependent phase of expansion, Foxo1 is inactivated by antigen receptor-mediated post-translational modifications. Here we show that in the late phase of expansion, Foxo1 was no longer post-translationally regulated but was inhibited post-transcriptionally by the interleukin 2 (IL-2)-induced microRNA miR-182. Specific inhibition of miR-182 in helper T lymphocytes limited their population expansion in vitro and in vivo. Our results demonstrate a central role for miR-182 in the physiological regulation of IL-2-driven helper T cell-mediated immune responses and open new therapeutic possibilities.
Subject(s)
Interleukin-2/immunology , MicroRNAs/immunology , T-Lymphocytes, Helper-Inducer/cytology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Arthritis/immunology , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BLABSTRACT
Dendritic cell (DC)-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN: CD209) is a C-type lectin that binds ICAM-2,3 and various pathogens such as HIV, helicobacter, and mycobacteria. It has been suggested that Mycobacterium tuberculosis, the causative agent of pulmonary tuberculosis, interacts with DC-SIGN to evade the immune system. To directly analyze the role of human DC-SIGN during mycobacterial infection, we generated conventional transgenic (tg) mice (termed "hSIGN") using CD209 cDNA under the control of the murine CD11c promoter. Upon mycobacterial infection, DCs from hSIGN mice produced significantly less IL-12p40 and no significant differences were be observed in the secretion levels of IL-10 relative to control DCs. After high dose aerosol infection with the strain M. tuberculosis H37Rv, hSIGN mice showed massive accumulation of DC-SIGN(+) cells in infected lungs, reduced tissue damage and prolonged survival. Based on our in vivo data, we propose that instead of favoring the immune evasion of mycobacteria, human DC-SIGN may have evolved as a pathogen receptor promoting protection by limiting tuberculosis-induced pathology.
