RESUMO
Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.
Assuntos
Interleucinas/genética , Interleucinas/metabolismo , Animais , Suscetibilidade a Doenças , Regulação da Expressão Gênica , Humanos , Interleucinas/química , Linfócitos/imunologia , Linfócitos/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Transdução de Sinais , Interleucina 22RESUMO
CD4 T follicular helper (TFH) cells support B cells, which are critical for germinal center (GC) formation, but the importance of TFH-B cell interactions in cancer is unclear. We found enrichment of TFH cell transcriptional signature correlates with GC B cell signature and with prolonged survival in individuals with lung adenocarcinoma (LUAD). We further developed a murine LUAD model in which tumor cells express B cell- and T cell-recognized neoantigens. Interactions between tumor-specific TFH and GC B cells, as well as interleukin (IL)-21 primarily produced by TFH cells, are necessary for tumor control and effector CD8 T cell function. Development of TFH cells requires B cells and B cell-recognized neoantigens. Thus, tumor neoantigens can regulate the fate of tumor-specific CD4 T cells by facilitating their interactions with tumor-specific B cells, which in turn promote anti-tumor immunity by enhancing CD8 T cell effector functions.
Assuntos
Adenocarcinoma/imunologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interleucinas/imunologia , Neoplasias Pulmonares/imunologia , Animais , Linfócitos B/citologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The ability of immune-modulating biologics to prevent and reverse pathology has transformed recent clinical practice. Full utility in the neuroinflammation space, however, requires identification of both effective targets for local immune modulation and a delivery system capable of crossing the blood-brain barrier. The recent identification and characterization of a small population of regulatory T (Treg) cells resident in the brain presents one such potential therapeutic target. Here, we identified brain interleukin 2 (IL-2) levels as a limiting factor for brain-resident Treg cells. We developed a gene-delivery approach for astrocytes, with a small-molecule on-switch to allow temporal control, and enhanced production in reactive astrocytes to spatially direct delivery to inflammatory sites. Mice with brain-specific IL-2 delivery were protected in traumatic brain injury, stroke and multiple sclerosis models, without impacting the peripheral immune system. These results validate brain-specific IL-2 gene delivery as effective protection against neuroinflammation, and provide a versatile platform for delivery of diverse biologics to neuroinflammatory patients.
Assuntos
Astrócitos , Produtos Biológicos , Animais , Encéfalo , Humanos , Interleucina-2/genética , Interleucinas , Camundongos , Doenças Neuroinflamatórias , Linfócitos T ReguladoresRESUMO
Rotavirus (RV) encounters intestinal epithelial cells amidst diverse microbiota, opening possibilities of microbes influencing RV infection. Although RV clearance typically requires adaptive immunity, we unintentionally generated RV-resistant immunodeficient mice, which, we hypothesized, reflected select microbes protecting against RV. Accordingly, such RV resistance was transferred by co-housing and fecal transplant. RV-protecting microbiota were interrogated by heat, filtration, and antimicrobial agents, followed by limiting dilution transplant to germ-free mice and microbiome analysis. This approach revealed that segmented filamentous bacteria (SFB) were sufficient to protect mice against RV infection and associated diarrhea. Such protection was independent of previously defined RV-impeding factors, including interferon, IL-17, and IL-22. Colonization of the ileum by SFB induced changes in host gene expression and accelerated epithelial cell turnover. Incubation of RV with SFB-containing feces reduced infectivity in vitro, suggesting direct neutralization of RV. Thus, independent of immune cells, SFB confer protection against certain enteric viral infections and associated diarrheal disease.
Assuntos
Imunidade Adaptativa/genética , Diarreia/microbiologia , Mucosa Intestinal/microbiologia , Infecções por Rotavirus/microbiologia , Animais , Anti-Infecciosos/farmacologia , Bactérias/genética , Bactérias/metabolismo , Diarreia/prevenção & controle , Diarreia/virologia , Fezes/microbiologia , Regulação da Expressão Gênica/genética , Humanos , Íleo/microbiologia , Íleo/patologia , Íleo/virologia , Interferons/genética , Interleucina-17/genética , Interleucinas/genética , Mucosa Intestinal/patologia , Mucosa Intestinal/virologia , Camundongos , Microbiota/genética , Rotavirus/patogenicidade , Infecções por Rotavirus/prevenção & controle , Infecções por Rotavirus/virologia , Interleucina 22RESUMO
Patients with myelodysplastic syndromes (MDSs) display severe anemia but the mechanisms underlying this phenotype are incompletely understood. Right open-reading-frame kinase 2 (RIOK2) encodes a protein kinase located at 5q15, a region frequently lost in patients with MDS del(5q). Here we show that hematopoietic cell-specific haploinsufficient deletion of Riok2 (Riok2f/+Vav1cre) led to reduced erythroid precursor frequency leading to anemia. Proteomic analysis of Riok2f/+Vav1cre erythroid precursors suggested immune system activation, and transcriptomic analysis revealed an increase in p53-dependent interleukin (IL)-22 in Riok2f/+Vav1cre CD4+ T cells (TH22). Further, we discovered that the IL-22 receptor, IL-22RA1, was unexpectedly present on erythroid precursors. Blockade of IL-22 signaling alleviated anemia not only in Riok2f/+Vav1cre mice but also in wild-type mice. Serum concentrations of IL-22 were increased in the subset of patients with del(5q) MDS as well as patients with anemia secondary to chronic kidney disease. This work reveals a possible therapeutic opportunity for reversing many stress-induced anemias by targeting IL-22 signaling.
Assuntos
Anemia/metabolismo , Anticorpos Neutralizantes/farmacologia , Células Eritroides/metabolismo , Eritropoese/efeitos dos fármacos , Interleucinas/antagonistas & inibidores , Síndromes Mielodisplásicas/tratamento farmacológico , Receptores de Interleucina/metabolismo , Anemia/sangue , Anemia/imunologia , Anemia/prevenção & controle , Animais , Células Cultivadas , Microambiente Celular , Modelos Animais de Doenças , Células Eritroides/imunologia , Humanos , Interleucinas/imunologia , Interleucinas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndromes Mielodisplásicas/sangue , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Receptores de Interleucina/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/imunologia , Insuficiência Renal Crônica/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Interleucina 22RESUMO
Cytokine signaling via signal transducer and activator of transcription (STAT) proteins is crucial for optimal antiviral responses of natural killer (NK) cells. However, the pleiotropic effects of both cytokine and STAT signaling preclude the ability to precisely attribute molecular changes to specific cytokine-STAT modules. Here, we employed a multi-omics approach to deconstruct and rebuild the complex interaction of multiple cytokine signaling pathways in NK cells. Proinflammatory cytokines and homeostatic cytokines formed a cooperative axis to commonly regulate global gene expression and to further repress expression induced by type I interferon signaling. These cytokines mediated distinct modes of epigenetic regulation via STAT proteins, and collective signaling best recapitulated global antiviral responses. The most dynamically responsive genes were conserved across humans and mice, which included a cytokine-STAT-induced cross-regulatory program. Thus, an intricate crosstalk exists between cytokine signaling pathways, which governs NK cell responses.
Assuntos
Epigênese Genética/imunologia , Infecções por Herpesviridae/imunologia , Interleucinas/metabolismo , Células Matadoras Naturais/imunologia , Fatores de Transcrição STAT/metabolismo , Animais , Separação Celular , Sequenciamento de Cromatina por Imunoprecipitação , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Redes Reguladoras de Genes/imunologia , Infecções por Herpesviridae/sangue , Infecções por Herpesviridae/virologia , Humanos , Imunidade Inata/genética , Células Matadoras Naturais/metabolismo , Masculino , Camundongos , Camundongos Knockout , Muromegalovirus/imunologia , Análise de Componente Principal , RNA-Seq , Fatores de Transcrição STAT/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologiaRESUMO
The IL-10 family of cytokines consists of nine members: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and the more distantly related IL-28A, IL-28B, and IL-29. Evolutionarily, IL-10 family cytokines emerged before the adaptive immune response. These cytokines elicit diverse host defense mechanisms, especially from epithelial cells, during various infections. IL-10 family cytokines are essential for maintaining the integrity and homeostasis of tissue epithelial layers. Members of this family can promote innate immune responses from tissue epithelia to limit the damage caused by viral and bacterial infections. These cytokines can also facilitate the tissue-healing process in injuries caused by infection or inflammation. Finally, IL-10 itself can repress proinflammatory responses and limit unnecessary tissue disruptions caused by inflammation. Thus, IL-10 family cytokines have indispensable functions in many infectious and inflammatory diseases.
Assuntos
Infecções/imunologia , Inflamação/imunologia , Interleucina-10/imunologia , Animais , Humanos , Interleucina-10/química , Interleucina-10/genética , Interleucinas/química , Interleucinas/genética , Interleucinas/imunologiaRESUMO
Cytokine expression during T cell differentiation is a highly regulated process that involves long-range promoter-enhancer and CTCF-CTCF contacts at cytokine loci. Here, we investigated the impact of dynamic chromatin loop formation within the topologically associating domain (TAD) in regulating the expression of interferon gamma (IFN-γ) and interleukin-22 (IL-22); these cytokine loci are closely located in the genome and are associated with complex enhancer landscapes, which are selectively active in type 1 and type 3 lymphocytes. In situ Hi-C analyses revealed inducible TADs that insulated Ifng and Il22 enhancers during Th1 cell differentiation. Targeted deletion of a 17 bp boundary motif of these TADs imbalanced Th1- and Th17-associated immunity, both in vitro and in vivo, upon Toxoplasma gondii infection. In contrast, this boundary element was dispensable for cytokine regulation in natural killer cells. Our findings suggest that precise cytokine regulation relies on lineage- and developmental stage-specific interactions of 3D chromatin architectures and enhancer landscapes.
Assuntos
Fator de Ligação a CCCTC , Diferenciação Celular , Interferon gama , Interleucina 22 , Interleucinas , Células Th1 , Animais , Fator de Ligação a CCCTC/metabolismo , Fator de Ligação a CCCTC/genética , Células Th1/imunologia , Camundongos , Diferenciação Celular/imunologia , Interferon gama/metabolismo , Sítios de Ligação , Interleucinas/metabolismo , Interleucinas/genética , Elementos Facilitadores Genéticos/genética , Camundongos Endogâmicos C57BL , Cromatina/metabolismo , Toxoplasmose/imunologia , Toxoplasmose/parasitologia , Toxoplasmose/genética , Regulação da Expressão Gênica , Toxoplasma/imunologia , Citocinas/metabolismo , Linhagem da Célula , Células Th17/imunologiaRESUMO
The small intestinal tuft cell-ILC2 circuit mediates epithelial responses to intestinal helminths and protists by tuft cell chemosensory-like sensing and IL-25-mediated activation of lamina propria ILC2s. Small intestine ILC2s constitutively express the IL-25 receptor, which is negatively regulated by A20 (Tnfaip3). A20 deficiency in ILC2s spontaneously triggers the circuit and, unexpectedly, promotes adaptive small-intestinal lengthening and remodeling. Circuit activation occurs upon weaning and is enabled by dietary polysaccharides that render mice permissive for Tritrichomonas colonization, resulting in luminal accumulation of acetate and succinate, metabolites of the protist hydrogenosome. Tuft cells express GPR91, the succinate receptor, and dietary succinate, but not acetate, activates ILC2s via a tuft-, TRPM5-, and IL-25-dependent pathway. Also induced by parasitic helminths, circuit activation and small intestinal remodeling impairs infestation by new helminths, consistent with the phenomenon of concomitant immunity. We describe a metabolic sensing circuit that may have evolved to facilitate mutualistic responses to luminal pathosymbionts.
Assuntos
Intestino Delgado/fisiologia , Tritrichomonas/metabolismo , Acetatos/metabolismo , Animais , Fibras na Dieta/metabolismo , Metabolismo Energético , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Células Epiteliais/parasitologia , Interleucinas/genética , Interleucinas/metabolismo , Mucosa Intestinal/citologia , Intestino Delgado/microbiologia , Intestino Delgado/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microbiota , Plasmídeos/genética , Plasmídeos/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Ácido Succínico/metabolismo , Canais de Cátion TRPM/metabolismo , Tritrichomonas/crescimento & desenvolvimento , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismoRESUMO
Interleukin-22 (IL-22) is a cytokine with pleotropic and opposing roles in physiological and pathological states. In this issue of Immunity, Giannou et al. and Briukhovetska et al. demonstrate how IL-22 is involved in promoting cancer metastasis formation.
Assuntos
Citocinas , Interleucinas , Interleucina 22RESUMO
Although T cells can exert potent anti-tumor immunity, a subset of T helper (Th) cells producing interleukin-22 (IL-22) in breast and lung tumors is linked to dismal patient outcome. Here, we examined the mechanisms whereby these T cells contribute to disease. In murine models of lung and breast cancer, constitutional and T cell-specific deletion of Il22 reduced metastases without affecting primary tumor growth. Deletion of the IL-22 receptor on cancer cells decreases metastasis to a degree similar to that seen in IL-22-deficient mice. IL-22 induced high expression of CD155, which bound to the activating receptor CD226 on NK cells. Excessive activation led to decreased amounts of CD226 and functionally impaired NK cells, which elevated the metastatic burden. IL-22 signaling was also associated with CD155 expression in human datasets and with poor patient outcomes. Taken together, our findings reveal an immunosuppressive circuit activated by T cell-derived IL-22 that promotes lung metastasis.
Assuntos
Interleucinas , Neoplasias , Receptores Virais , Linfócitos T Auxiliares-Indutores , Animais , Humanos , Camundongos , Antígenos de Diferenciação de Linfócitos T/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Células Matadoras Naturais/metabolismo , Neoplasias/metabolismo , Ligação Proteica , Linfócitos T Auxiliares-Indutores/metabolismo , Interleucina 22RESUMO
During metastasis, cancer cells invade, intravasate, enter the circulation, extravasate, and colonize target organs. Here, we examined the role of interleukin (IL)-22 in metastasis. Immune cell-derived IL-22 acts on epithelial tissues, promoting regeneration and healing upon tissue damage, but it is also associated with malignancy. Il22-deficient mice and mice treated with an IL-22 antibody were protected from colon-cancer-derived liver and lung metastasis formation, while overexpression of IL-22 promoted metastasis. Mechanistically, IL-22 acted on endothelial cells, promoting endothelial permeability and cancer cell transmigration via induction of endothelial aminopeptidase N. Multi-parameter flow cytometry and single-cell sequencing of immune cells isolated during cancer cell extravasation into the liver revealed iNKT17 cells as source of IL-22. iNKT-cell-deficient mice exhibited reduced metastases, which was reversed by injection of wild type, but not Il22-deficient, invariant natural killer T (iNKT) cells. IL-22-producing iNKT cells promoting metastasis were tissue resident, as demonstrated by parabiosis. Thus, IL-22 may present a therapeutic target for prevention of metastasis.
Assuntos
Interleucinas , Neoplasias Hepáticas , Células T Matadoras Naturais , Animais , Camundongos , Células Endoteliais/metabolismo , Interleucinas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/metabolismo , Neoplasias Colorretais/metabolismo , Interleucina 22RESUMO
Regulatory T cells (Treg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8+ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8+ TILs that limits effective anti-tumor immunity.
Assuntos
Imunidade Celular , Interleucina-10/metabolismo , Interleucinas/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Transferência Adotiva , Animais , Citocinas/genética , Citocinas/metabolismo , Perfilação da Expressão Gênica , Humanos , Melanoma Experimental , Camundongos , Neoplasias/patologia , Transdução de Sinais , TranscriptomaRESUMO
Innate lymphoid cells (ILCs) are tissue-resident lymphocytes categorized on the basis of their core regulatory programs and the expression of signature cytokines. Human ILC3s that produce the cytokine interleukin-22 convert into ILC1-like cells that produce interferon-γ in vitro, but whether this conversion occurs in vivo remains unclear. In the present study we found that ILC3s and ILC1s in human tonsils represented the ends of a spectrum that included additional discrete subsets. RNA velocity analysis identified an intermediate ILC3-ILC1 cluster, which had strong directionality toward ILC1s. In humanized mice, the acquisition of ILC1 features by ILC3s showed tissue dependency. Chromatin studies indicated that the transcription factors Aiolos and T-bet cooperated to repress regulatory elements active in ILC3s. A transitional ILC3-ILC1 population was also detected in the human intestine. We conclude that ILC3s undergo conversion into ILC1-like cells in human tissues in vivo, and that tissue factors and Aiolos were required for this process.
Assuntos
Imunidade Inata/imunologia , Interferon gama/metabolismo , Interleucinas/metabolismo , Mucosa Intestinal/imunologia , Linfócitos/imunologia , Tonsila Palatina/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Criança , Pré-Escolar , Humanos , Fator de Transcrição Ikaros/metabolismo , Mucosa Intestinal/citologia , Linfócitos/classificação , Linfócitos/citologia , Camundongos , Proteínas com Domínio T/metabolismo , Interleucina 22RESUMO
Interferon-λ (IFN-λ) acts on mucosal epithelial cells and thereby confers direct antiviral protection. In contrast, the role of IFN-λ in adaptive immunity is far less clear. Here, we report that mice deficient in IFN-λ signaling exhibited impaired CD8+ T cell and antibody responses after infection with a live-attenuated influenza virus. Virus-induced release of IFN-λ triggered the synthesis of thymic stromal lymphopoietin (TSLP) by M cells in the upper airways that, in turn, stimulated migratory dendritic cells and boosted antigen-dependent germinal center reactions in draining lymph nodes. The IFN-λ-TSLP axis also boosted production of the immunoglobulins IgG1 and IgA after intranasal immunization with influenza virus subunit vaccines and improved survival of mice after challenge with virulent influenza viruses. IFN-λ did not influence the efficacy of vaccines applied by subcutaneous or intraperitoneal routes, indicating that IFN-λ plays a vital role in potentiating adaptive immune responses that initiate at mucosal surfaces.
Assuntos
Imunidade Adaptativa/imunologia , Citocinas/imunologia , Imunidade nas Mucosas/imunologia , Interleucinas/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Imunidade Adaptativa/genética , Animais , Formação de Anticorpos/efeitos dos fármacos , Formação de Anticorpos/imunologia , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/virologia , Imunidade nas Mucosas/efeitos dos fármacos , Imunidade nas Mucosas/genética , Imunização/métodos , Vírus da Influenza A/efeitos dos fármacos , Vírus da Influenza A/imunologia , Vírus da Influenza A/fisiologia , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Interleucinas/administração & dosagem , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/prevenção & controle , Infecções por Orthomyxoviridae/virologia , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Receptores de Interferon/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity.
Assuntos
Sinapses Imunológicas , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Centro Germinativo , InterleucinasRESUMO
CD4+ T cell-derived interleukin 21 (IL-21) sustains CD8+ T cell responses during chronic viral infection, but the helper subset that confers this protection remains unclear. Here, we applied scRNA and ATAC-seq approaches to determine the heterogeneity of IL-21+CD4+ T cells during LCMV clone 13 infection. CD4+ T cells were comprised of three transcriptionally and epigenetically distinct populations: Cxcr6+ Th1 cells, Cxcr5+ Tfh cells, and a previously unrecognized Slamf6+ memory-like (Tml) subset. T cell differentiation was specifically redirected toward the Tml subset during chronic, but not acute, LCMV infection. Although this subset displayed an enhanced capacity to accumulate and some developmental plasticity, it remained largely quiescent, which may hinder its helper potential. Conversely, mixed bone marrow chimera experiments revealed that Tfh cell-derived IL-21 was critical to sustain CD8+ T cell responses and viral control. Thus, strategies that bolster IL-21+Tfh cell responses may prove effective in enhancing CD8+ T cell-mediated immunity.
Assuntos
Células T Auxiliares Foliculares , Viroses , Linfócitos T CD8-Positivos , Humanos , InterleucinasRESUMO
Interleukin (IL)-22 is central to immune defense at barrier sites. We examined the contributions of innate lymphoid cell (ILC) and T cell-derived IL-22 during Citrobacter rodentium (C.r) infection using mice that both report Il22 expression and allow lineage-specific deletion. ILC-derived IL-22 activated STAT3 in C.r-colonized surface intestinal epithelial cells (IECs) but only temporally restrained bacterial growth. T cell-derived IL-22 induced a more robust and extensive activation of STAT3 in IECs, including IECs lining colonic crypts, and T cell-specific deficiency of IL-22 led to pathogen invasion of the crypts and increased mortality. This reflected a requirement for T cell-derived IL-22 for the expression of a host-protective transcriptomic program that included AMPs, neutrophil-recruiting chemokines, and mucin-related molecules, and it restricted IFNγ-induced proinflammatory genes. Our findings demonstrate spatiotemporal differences in the production and action of IL-22 by ILCs and T cells during infection and reveal an indispensable role for IL-22-producing T cells in the protection of the intestinal crypts.
Assuntos
Citrobacter rodentium , Infecções por Enterobacteriaceae , Animais , Antibacterianos , Imunidade Inata , Interleucinas/metabolismo , Mucosa Intestinal , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/metabolismo , Interleucina 22RESUMO
The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe-/- and Ldlr-/- mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3+ follicular helper T cells (TFH cells). TFH cells isolated from Apoe-/- mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3+ TFH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased TFH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune TFH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner.
Assuntos
Aterosclerose/imunologia , Dislipidemias/imunologia , Interleucinas/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Camundongos , Camundongos Knockout , Receptor 4 Toll-Like/imunologiaRESUMO
The interleukin (IL)-17 family, consisting of six members, promotes host defense but can in some context promote the development of autoimmune disease. Here, we examined the role of IL-17D, a poorly understood member in the IL-17 family. IL-17D was expressed primarily by colonic epithelial cells. Il17d-/- mice were more susceptible to acute colitis, bacterial infection and experimentally induced colon cancer than their wildtype counterparts. Il17d deficiency impaired IL-22 production by group 3 innate lymphoid cells (ILC3s) and reduced expression of IL-22-dependent antimicrobial peptides, RegIIIß and RegIIIγ, in colon tissue at steady state and in colitis; this was associated with changes in microbial composition and dysbiosis. Protein purification studies revealed that IL-17D bound not canonical IL-17 receptors, but rather CD93, a glycoprotein expressed on mature ILC3s. Mice lacking Cd93 in ILC3s exhibited impaired IL-22 production and aggravated colonic inflammation in experimental colitis. Thus, an IL-17D-CD93 axis regulates ILC3 function to preserve intestinal homeostasis.