RESUMEN
RATIONALE: Pulmonary complications of hematopoietic stem cell transplantation include infections and graft-versus-host diseases, such as idiopathic pneumonia syndrome (IPS). Conflicting data exist regarding the role of the interferon (IFN)-gamma-producing Th1 CD4(+) T-cell subset and IL-17A in IPS. OBJECTIVES: To determine the role of IFN-gamma and IL-17A in the establishment of pulmonary graft-versus-host disease. METHODS: A semiallogeneic murine model based on C57BL/6 x BALB/c as recipients with transplantation of BALB/c RAG2(-/-) bone marrow and transfer of different genetic knockout T cells (T-bet(-/-), IFN-gamma(-/-), IFN-gammaR(-/-)) on a BALB/c background. Lung tissue was examined for parenchymal changes and infiltrating cells by histology and fluorescence-activated cell sorter analysis. MEASUREMENTS AND MAIN RESULTS: After transfer of semiallogeneic bone marrow together with donor CD4(+) T cells lacking IFN-gamma or T-bet-a T-box transcription factor controlling Th1 commitment-we found severe inflammation in the lungs, but no enhancement in other organs. In contrast, wild-type donor CD4(+) T cells mediated minimal inflammation only, and donor CD8(+) T cells were not required for IPS development. Mechanistically, the absence of IFN-gamma or IFN-gamma signaling in pulmonary parenchymal cells promoted expansion of IL-17A-producing CD4(+) T cells and local IL-17A release. In vivo depletion of IL-17A reduced disease severity. CONCLUSIONS: One mechanism of IFN-gamma protection against IPS is negative regulation of the expansion of pathogenic IL-17A-producing CD4(+) T cells through interaction with the IFN-gamma receptor on the pulmonary parenchymal cell population.
Asunto(s)
Trasplante de Médula Ósea/inmunología , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/inmunología , Interferón gamma/fisiología , Interleucina-17/sangre , Neumonía/inmunología , Células TH1/inmunología , Animales , Trasplante de Médula Ósea/patología , Enfermedad Injerto contra Huésped/patología , Pulmón/inmunología , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía/patología , Receptores de Interferón/fisiología , Síndrome , Proteínas de Dominio T Box/fisiología , Receptor de Interferón gammaRESUMEN
Experimental autoimmune myocarditis (EAM) represents a Th17 T cell-mediated mouse model of postinflammatory heart disease. In BALB/c wild-type mice, EAM is a self-limiting disease, peaking 21 days after alpha-myosin H chain peptide (MyHC-alpha)/CFA immunization and largely resolving thereafter. In IFN-gammaR(-/-) mice, however, EAM is exacerbated and shows a chronic progressive disease course. We found that this progressive disease course paralleled persistently elevated IL-17 release from T cells infiltrating the hearts of IFN-gammaR(-/-) mice 30 days after immunization. In fact, IL-17 promoted the recruitment of CD11b(+) monocytes, the major heart-infiltrating cells in EAM. In turn, CD11b(+) monocytes suppressed MyHC-alpha-specific Th17 T cell responses IFN-gamma-dependently in vitro. In vivo, injection of IFN-gammaR(+/+)CD11b(+), but not IFN-gammaR(-/-)CD11b(+), monocytes, suppressed MyHC-alpha-specific T cells, and abrogated the progressive disease course in IFN-gammaR(-/-) mice. Finally, coinjection of MyHC-alpha-specific, but not OVA-transgenic, IFN-gamma-releasing CD4(+) Th1 T cell lines, together with MyHC-alpha-specific Th17 T cells protected RAG2(-/-) mice from EAM. In conclusion, CD11b(+) monocytes play a dual role in EAM: as a major cellular substrate of IL-17-induced inflammation and as mediators of an IFN-gamma-dependent negative feedback loop confining disease progression.
Asunto(s)
Enfermedades Autoinmunes/prevención & control , Antígeno CD11b/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Interleucina-17/administración & dosificación , Interleucina-17/antagonistas & inhibidores , Monocitos/inmunología , Miocarditis/inmunología , Miocarditis/prevención & control , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/patología , Línea Celular , Movimiento Celular/inmunología , Separación Celular , Progresión de la Enfermedad , Retroalimentación Fisiológica/inmunología , Sueros Inmunes/administración & dosificación , Interleucina-17/inmunología , Depleción Linfocítica , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Ratones Mutantes , Ratones Transgénicos , Datos de Secuencia Molecular , Monocitos/citología , Monocitos/metabolismo , Miocarditis/patología , Células TH1/inmunologíaRESUMEN
Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)-gamma production, develop severe autoimmune heart disease compared to T-bet+/+ control mice. Experiments in T-bet-/- IL-4-/- and T-bet-/- IL-4Ralpha-/- mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet-/- IL-12Rbeta1-/- and T-bet-/- IL-12p35-/- mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet-/- mice showed a marked increase in production of the IL-23-dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet-/- mice. Heart-infiltrating T-bet-/- CD8+ but not CD8- T cells secrete IFN-gamma, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet-/- CD8+ lymphocytes completely lost their capacity to release IFN-gamma within the heart. Collectively, these data show that severe IL-17-mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8+ T cell bystander functions in the inflamed target organ.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Interleucina-17/biosíntesis , Miocarditis/inmunología , Factores de Transcripción/metabolismo , Animales , Enfermedades Autoinmunes/metabolismo , Autoinmunidad/inmunología , Médula Ósea , Complejo CD3/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Citocinas/biosíntesis , Células Dendríticas/citología , Células Dendríticas/inmunología , Humanos , Inmunización , Interleucina-17/deficiencia , Interleucina-23 , Subunidad p19 de la Interleucina-23 , Interleucinas/biosíntesis , Tejido Linfoide/inmunología , Ratones , Ratones SCID , Miocarditis/metabolismo , Miocardio/citología , Miocardio/patología , Receptores de Interleucina-2/inmunología , Proteínas de Dominio T Box , Linfocitos T Reguladores/inmunología , Células TH1/citología , Células TH1/inmunología , Células Th2/citología , Células Th2/inmunología , Factores de Transcripción/deficienciaRESUMEN
BACKGROUND: Experimental autoimmune myocarditis (EAM) is a CD4+ T-cell-mediated mouse model of postviral cardiomyopathy. Activation of interleukin-1 type 1 and Toll-like receptors that share the common downstream adaptor molecule MyD88 is required for disease induction. The specific role of MyD88 in myocarditis, however, is not known. METHODS AND RESULTS: In contrast to control littermates, MyD88(-/-) mice were protected from myocarditis after immunization with alpha-myosin heavy chain-derived peptide (MyHC-alpha) and complete Freund's adjuvant. Disease resistance of MyD88(-/-) mice resulted from impaired expansion of heart-specific CD4+ T cells after immunization. Intrinsic defects of MyD88(-/-) CD4+ T cells were excluded. In contrast, MyD88(-/-) but not MyD88(+/+) primary antigen presenting dendritic cells (DCs) were defective in their capacity to prime CD4+ T cells. This defect mainly resulted from the inability of MyD88(-/-) DCs to release tumor necrosis factor-alpha. The critical role of MyD88 signaling in DCs in the peripheral lymphatic compartments was finally proven by repetitive injection of activated, MyHC-alpha-loaded MyD88(+/+) DCs that fully restored T-cell expansion and myocarditis in MyD88(-/-) mice. CONCLUSIONS: Autoimmune myocarditis induction depends on MyD88 signaling in self-antigen presenting cells in the peripheral compartments. We conclude that MyD88 might become a target for prevention of heart-specific autoimmunity and cardiomyopathy.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Enfermedades Autoinmunes/etiología , Miocarditis/etiología , Transducción de Señal/fisiología , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Autoantígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide , Miocarditis/inmunología , Cadenas Pesadas de Miosina/administración & dosificación , Cadenas Pesadas de Miosina/inmunología , Miosinas Ventriculares/administración & dosificación , Miosinas Ventriculares/inmunologíaRESUMEN
Systemic lupus erythematosus (SLE), which is characterized by the increased production of autoantibodies and defective T cell responses, can be induced in mice by immunization with a human anti-DNA mAb that expresses a major Id, designated 16/6Id. A peptide based on the sequence of the CDR1 of the 16/6Id (human CDR1 (hCDR1)) ameliorated the clinical manifestations of SLE and down-regulated, ex vivo, the 16/6Id-induced T cell proliferation. In this study, we examined the mechanism responsible for the hCDR1-induced modulation of T cell functions related to the pathogenesis of SLE. We found that injection of hCDR1 into BALB/c mice concomitant with their immunization with 16/6Id resulted in a marked elevation of TGF-beta secretion 10 days later. Addition of TGF-beta suppressed the 16/6Id-stimulated T cell proliferation similarly to hCDR1. In addition, we provide evidence that one possible mechanism underlying the hCDR1- and TGFbeta-induced inhibition of T cell proliferation is by down-regulating the expression, and therefore the functions, of a pair of key cell adhesion receptors, LFA-1 (alphaLbeta2) and CD44, which operate as accessory molecules in mediating APC-T cell interactions. Indeed, T cells of mice treated with hCDR1 showed a TGF-beta-induced suppression of adhesion to the LFA-1 and CD44 ligands, hyaluronic acid and ICAM-1, respectively, induced by stromal cell-derived factor-1alpha and PMA. The latter suppression is through the inhibition of ERK phosphorylation. Thus, the down-regulation of SLE-associated responses by hCDR1 treatment may be due to the effect of the up-regulated TGF-beta on the expression and function of T cell adhesion receptors and, consequently, on T cell stimulation, adhesion, and proliferation.