RESUMO
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.
Assuntos
Interleucina-2/imunologia , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Artrite/imunologia , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
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.
Assuntos
Núcleo Celular/metabolismo , Regulação da Expressão Gênica/fisiologia , Interleucina-4/biossíntese , Fatores de Transcrição NFATC/metabolismo , Elementos de Resposta/fisiologia , Células Th2/metabolismo , Transporte Ativo do Núcleo Celular/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Núcleo Celular/genética , Núcleo Celular/imunologia , DNA Helicases/genética , DNA Helicases/imunologia , DNA Helicases/metabolismo , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/imunologia , Proteína p300 Associada a E1A/metabolismo , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/imunologia , Fator de Transcrição GATA3/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Fosforilação/fisiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Fator de Transcrição STAT6/genética , Fator de Transcrição STAT6/imunologia , Fator de Transcrição STAT6/metabolismo , Células Th2/citologia , Células Th2/imunologia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/imunologia , Fator de Transcrição RelA/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismoRESUMO
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.