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[This corrects the article DOI: 10.1371/journal.pone.0076451.].
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During allogeneic hematopoietic cell transplantation (alloHCT), nonhematopoietic cell interleukin-33 (IL-33) is augmented and released by recipient conditioning to promote type 1 alloimmunity and lethal acute graft-versus-host disease (GVHD). Yet, IL-33 is highly pleiotropic and exhibits potent immunoregulatory properties in the absence of coincident proinflammatory stimuli. We tested whether peri-alloHCT IL-33 delivery can protect against development of GVHD by augmenting IL-33-associated regulatory mechanisms. IL-33 administration augmented the frequency of regulatory T cells (Tregs) expressing the IL-33 receptor, suppression of tumorigenicity-2 (ST2), which persist following total body irradiation. ST2 expression is not exclusive to Tregs and IL-33 expands innate immune cells with regulatory or reparative properties. However, selective depletion of recipient Foxp3(+) cells concurrent with peri-alloHCT IL-33 administration accelerated acute GVHD lethality. IL-33-expanded Tregs protected recipients from GVHD by controlling macrophage activation and preventing accumulation of effector T cells in GVHD-target tissue. IL-33 stimulation of ST2 on Tregs activates p38 MAPK, which drives expansion of the ST2(+) Treg subset. Associated mechanistic studies revealed that proliferating Tregs exhibit IL-33-independent upregulation of ST2 and the adoptive transfer of st2(+) but not st2(-) Tregs mediated GVHD protection. In total, these data demonstrate the protective capacity of peri-alloHCT administration of IL-33 and IL-33-responsive Tregs in mouse models of acute GVHD. These findings provide strong support that the immunoregulatory relationship between IL-33 and Tregs can be harnessed therapeutically to prevent GVHD after alloHCT for treatment of malignancy or as a means for tolerance induction in solid organ transplantation.
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Enfermedad Injerto contra Huésped/prevención & control , Proteína 1 Similar al Receptor de Interleucina-1/inmunología , Interleucina-33/inmunología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Trasplante de Células Madre de Sangre Periférica , Enfermedad Aguda , Aloinjertos , Animales , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/patología , Proteína 1 Similar al Receptor de Interleucina-1/genética , Activación de Macrófagos/genética , Macrófagos/patología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Receptores de Interleucina/genética , Receptores de Interleucina/inmunología , Linfocitos T ReguladoresRESUMEN
IL-33 is a more recently identified member of the IL-1 cytokine family, expressed in the nucleus of epithelial cells and released into the extracellular space following tissue damage. The impact of IL-33 as a regulator of the adaptive immune response has been studied extensively, with an understood role for IL-33 in the effector functions of CD4(+) Th2 cells. IL-33, however, is now being shown to initiate the Th2-polarizing function of DCs, and stimulate the secretion of the type 2-associated cytokines, IL-4, IL-5, and IL-13, from tissue-resident innate-immune cells, especially ILCs and MCs. IL-33 also initiates and perpetuates local inflammatory responses through the recruitment and activation of type 2- and inflammatory-associated effectors, such as eosinophils, basophils, and neutrophils. As such, IL-33 drives and amplifies type 2-dependent immunity, as well as type 2-dependent tissue destruction and inflammation. It is also becoming apparent that IL-33 supports the reparative capacity of macrophage and ILCs, but these functions may also contribute to chronic fibrotic diseases. Herein, we review new developments in the understanding of IL-33 as it functions in Th2 cells and type 2 immunity. This includes a discussion of our evolving understanding of how IL-33 directly and indirectly promotes type 2 immune responses through action on innate cells in immunity and the pathogenesis of atopic and fibrotic diseases.
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Inmunidad Adaptativa , Células Dendríticas/inmunología , Células Epiteliales/inmunología , Interleucinas/inmunología , Células Th2/inmunología , Animales , Células Dendríticas/patología , Células Epiteliales/patología , Fibrosis , Regulación de la Expresión Génica , Granulocitos/inmunología , Granulocitos/patología , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/genética , Macrófagos/inmunología , Macrófagos/patología , Proteínas Quinasas Activadas por Mitógenos/genética , Proteínas Quinasas Activadas por Mitógenos/inmunología , FN-kappa B/genética , FN-kappa B/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/inmunología , Transducción de Señal , Células Th2/patologíaRESUMEN
IL-33 is a recently characterized IL-1 family member that is proposed to function as an alarmin, or endogenous signal of cellular damage, as well as act as a pleiotropic cytokine. The ability of IL-33 to potentiate both Th1 and Th2 immunity supports its role in pathogen clearance and disease immunopathology. Yet, IL-33 restrains experimental colitis and transplant rejection by expanding regulatory T cells (Treg) via an undefined mechanism. We sought to determine the influence of IL-33 on hematopoietic cells that drives Treg expansion and underlies the therapeutic benefit of IL-33 administration. In this study, we identify a feedback loop in which conventional mouse CD11c(+) dendritic cells (DC) stimulated by IL-33 secrete IL-2 to selectively expand IL-33R(ST2(+))- suppressive CD4(+)Foxp3(+) Treg. Interestingly, this occurs in the absence of classical DC maturation, and DC-derived (innate) IL-2 increases ST2 expression on both DC and interacting Treg. ST2(+) Treg represent an activated subset of Foxp3(+) cells, demonstrated to be ICOS(high)CD44(high) compared with their ST2(-) counterparts. Furthermore, although studies have shown that IL-33-exposed DC promote Th2 responses, we reveal that ST2(+) DC are required for IL-33-mediated in vitro and in vivo Treg expansion. Thus, we have uncovered a relationship between IL-33 and innate IL-2 that promotes the selective expansion of ST2(+) Treg over non-Treg. These findings identify a novel regulatory pathway driven by IL-33 in immune cells that may be harnessed for therapeutic benefit or for robust expansion of Treg in vitro and in vivo.
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Células Dendríticas/efectos de los fármacos , Interleucina-2/metabolismo , Interleucinas/farmacología , Linfocitos T Reguladores/inmunología , Animales , Células Cultivadas , Células Dendríticas/inmunología , Factores de Transcripción Forkhead/biosíntesis , Receptores de Hialuranos/biosíntesis , Proteína Coestimuladora de Linfocitos T Inducibles/biosíntesis , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina/biosíntesis , Transducción de Señal/inmunología , Células TH1/inmunología , Células Th2/inmunologíaRESUMEN
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models. METHODS: Col(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses. RESULTS: Compared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-ß, Il-1ß, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-ß superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb). CONCLUSIONS: Anti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- ß-related signaling pathways.
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Colágeno Tipo V/inmunología , Tolerancia Inmunológica , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/inmunología , Transcripción Genética , Factor de Crecimiento Transformador beta/genética , Animales , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Bleomicina/efectos adversos , Colágeno Tipo I/inmunología , Colágeno Tipo V/administración & dosificación , Colágeno Tipo V/genética , Colágeno Tipo V/metabolismo , Citocinas/biosíntesis , Citocinas/genética , Modelos Animales de Enfermedad , Femenino , Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/inmunología , Fibrosis Pulmonar Idiopática/metabolismo , Fibrosis Pulmonar Idiopática/patología , Mediadores de Inflamación/metabolismo , Activación de Linfocitos/inmunología , Ratones , Nebulizadores y Vaporizadores , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Transcripción Genética/efectos de los fármacos , Factor de Crecimiento Transformador beta/biosíntesisAsunto(s)
Colágeno Tipo V/inmunología , Tolerancia Inmunológica/inmunología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/prevención & control , Adulto , Animales , Asma/sangre , Asma/inmunología , Asma/prevención & control , Colágeno Tipo V/sangre , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Hipersensibilidad Respiratoria/sangreRESUMEN
Extracellular antigens are internalized and processed before binding MHC class II molecules within endosomal and lysosomal compartments of professional antigen presenting cells (APC) for subsequent presentation to T cells. Yet select cytoplasmic peptides derived from autoantigens also intersect and bind class II molecules via an unknown mechanism. In human B lymphoblasts, inhibition of the peptide transporter associated with antigen processing (TAP) failed to alter class II-restricted cytoplasmic epitope presentation. By contrast, decreased display of cytoplasmic epitopes via class II molecules was observed in cells with diminished expression of the lysosome-associated membrane protein-2 (Lamp-2). Overexpression of Lamp-2 isoform A (Lamp-2a), an established component of chaperone-mediated autophagy, enhanced cytoplasmic autoantigen presentation. Manipulating APC expression of heat shock cognate protein 70 (hsc70), a cofactor for Lamp-2a, also altered cytoplasmic class II peptide presentation. These results demonstrate a novel role for the lysosomal Lamp-2a-hsc70 complex in promoting immunological recognition and antigen presentation.