RESUMO
Sexual satisfaction is critical for relationship quality and people hold lay beliefs (implicit theories) about what makes for satisfying sex. A common belief in Western culture is that spontaneous sex is most satisfying, but this idea has not yet been studied. In pre-registered analyses of two studies - a cross sectional (N = 303 individuals) and a 21-day daily experience study (N = 121 couples) - we found support for two distinct beliefs (spontaneous sex as satisfying; planned sex as satisfying). Across both studies, people held stronger beliefs that spontaneous sex is satisfying compared to planned sex, but stronger spontaneous sex beliefs were only associated with higher sexual satisfaction in Study 1. In Study 1, when people perceived their most recent sexual experience as planned (versus spontaneous), they felt less sexually satisfied, but this was not the case for those who endorsed stronger planned sex beliefs. In Study 2, endorsing stronger planned sex beliefs was associated with a partner's lower sexual satisfaction at baseline. There were no associations between perceptions of the extent to which sex was spontaneous and sexual satisfaction at baseline or in daily life. Future research could test whether beliefs about spontaneity and planning have value in clinical settings.
Assuntos
Orgasmo , Parceiros Sexuais , Humanos , Estudos Transversais , Relações Interpessoais , Comportamento Sexual , Satisfação PessoalRESUMO
Prostate cancer is generally considered an immunologically "cold" tumor type that is insensitive to immunotherapy. Targeting surface antigens on tumors through cellular therapy can induce a potent antitumor immune response to "heat up" the tumor microenvironment. However, many antigens expressed on prostate tumor cells are also found on normal tissues, potentially causing on-target, off-tumor toxicities and a suboptimal therapeutic index. Our studies revealed that six-transmembrane epithelial antigen of prostate-2 (STEAP2) was a prevalent prostate cancer antigen that displayed high, homogeneous cell surface expression across all stages of disease with limited distal normal tissue expression, making it ideal for therapeutic targeting. A multifaceted lead generation approach enabled development of an armored STEAP2 chimeric antigen receptor T cell (CAR-T) therapeutic candidate, AZD0754. This CAR-T product was armored with a dominant-negative TGF-ß type II receptor, bolstering its activity in the TGF-ß-rich immunosuppressive environment of prostate cancer. AZD0754 demonstrated potent and specific cytotoxicity against antigen-expressing cells in vitro despite TGF-ß-rich conditions. Further, AZD0754 enforced robust, dose-dependent in vivo efficacy in STEAP2-expressing cancer cell line-derived and patient-derived xenograft mouse models, and exhibited encouraging preclinical safety. Together, these data underscore the therapeutic tractability of STEAP2 in prostate cancer as well as build confidence in the specificity, potency, and tolerability of this potentially first-in-class CAR-T therapy.
Assuntos
Neoplasias da Próstata , Receptores de Antígenos Quiméricos , Masculino , Humanos , Camundongos , Animais , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva , Neoplasias da Próstata/patologia , Linfócitos T , Fator de Crescimento Transformador beta/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Microambiente Tumoral , Oxirredutases/metabolismoRESUMO
Treatment with anti-PD-1 and anti-PD-L1 therapies has shown durable clinical benefit in non-small cell lung cancer (NSCLC). However, patients with NSCLC with epidermal growth factor receptor (EGFR) mutations do not respond as well to treatment as patients without an EGFR mutation. We show that EGFR-mutated NSCLC expressed higher levels of CD73 compared with EGFR WT tumors and that CD73 expression was regulated by EGFR signaling. EGFR-mutated cell lines were significantly more resistant to T cell killing compared with WT cell lines through suppression of T cell proliferation and function. In a xenograft mouse model of EGFR-mutated NSCLC, neither anti-PD-L1 nor anti-CD73 antibody alone inhibited tumor growth compared with the isotype control. In contrast, the combination of both antibodies significantly inhibited tumor growth, increased the number of tumor-infiltrating CD8+ T cells, and enhanced IFN-γ and TNF-α production of these T cells. Consistently, there were increases in gene expression that corresponded to inflammation and T cell function in tumors treated with the combination of anti-PD-L1 and anti-CD73. Together, these results further support the combination of anti-CD73 and anti-PD-L1 therapies in treating EGFR-mutated NSCLC, while suggesting that increased T cell activity may play a role in response to therapy.
Assuntos
5'-Nucleotidase , Linfócitos T CD8-Positivos , Carcinoma Pulmonar de Células não Pequenas , Receptores ErbB , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Mutação , Animais , Feminino , Humanos , Camundongos , 5'-Nucleotidase/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , DNA de Neoplasias/genética , Quimioterapia Combinada , Receptores ErbB/genética , Receptores ErbB/metabolismo , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos SCID , Neoplasias Experimentais , Transdução de SinaisRESUMO
Sexuality is a key predictor of relationship satisfaction, but sexual desire and satisfaction can be difficult to maintain over time. Past research has investigated who might be more likely to experience higher (compared to lower) levels of desire and sexual satisfaction in their relationships. Certain aspects of personality, such as extraversion, have been associated with sexual satisfaction and desire, but evidence linking personality to sexual outcomes has generally been mixed, meaning there is a lot left to learn about how personality is associated with sexual well-being. A promising, yet unexplored, trait that could be associated with higher sexual desire and satisfaction is charisma-a combination of influence and affability that has been identified as a desirable trait when people are selecting a romantic or sexual partner. Across two studies-a cross-sectional study of individuals in relationships (N = 413) and a 21-day dyadic daily experience study (N = 121 couples)-people higher in charisma reported being more communal during sex and reported higher sexual desire and satisfaction. Through higher sexual communal strength, people with a charismatic partner also reported higher daily sexual desire and sexual satisfaction. The effects were largely retained above and beyond general communal strength and Big Five personality dimensions, although in Study 1, charisma was no longer associated with sexual desire and satisfaction when controlling for extraversion. The current findings provide initial evidence that charismatic people tend to be responsive to their partner's sexual needs, which is associated with higher desire and sexual satisfaction in romantic relationships.
Assuntos
Libido , Satisfação Pessoal , Estudos Transversais , Humanos , Relações Interpessoais , Comportamento Sexual , Parceiros SexuaisRESUMO
The decreasing cost of DNA sequencing over the past decade has led to an explosion of sequencing datasets, leaving us with petabytes of data to analyze. However, current sequencing visualization tools are designed to run on single machines, which limits their scalability and interactivity on modern genomic datasets. Here, we leverage the scalability of Apache Spark to provide Mango, consisting of a Jupyter notebook and genome browser, which removes scalability and interactivity constraints by leveraging multi-node compute clusters to allow interactive analysis over terabytes of sequencing data. We demonstrate scalability of the Mango tools by performing quality control analyses on 10 terabytes of 100 high-coverage sequencing samples from the Simons Genome Diversity Project, enabling capability for interactive genomic exploration of multi-sample datasets that surpass the computational limitations of single-node visualization tools. Mango is freely available for download with full documentation at https://bdg-mango.readthedocs.io/en/latest/.
Assuntos
Genômica/métodos , Análise de Sequência de DNA/métodos , Algoritmos , Big Data , Análise de Dados , Genoma/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , SoftwareRESUMO
Diet has been suggested to be a potential environmental risk factor for the increasing incidence of autoimmune diseases, yet the underlying mechanisms remain elusive. Here, we show that high glucose intake exacerbated autoimmunity in mouse models of colitis and experimental autoimmune encephalomyelitis (EAE). We elucidated that high amounts of glucose specifically promoted T helper-17 (Th17) cell differentiation by activating transforming growth factor-ß (TGF-ß) from its latent form through upregulation of reactive oxygen species (ROS) in T cells. We further determined that mitochondrial ROS (mtROS) are key for high glucose-induced TGF-ß activation and Th17 cell generation. We have thus revealed a previously unrecognized mechanism underlying the adverse effects of high glucose intake in the pathogenesis of autoimmunity and inflammation.
Assuntos
Ingestão de Alimentos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Glucose/metabolismo , Mitocôndrias/metabolismo , Esclerose Múltipla/imunologia , Células Th17/imunologia , Animais , Autoimunidade , Diferenciação Celular , Células Cultivadas , Dieta , Modelos Animais de Doenças , Humanos , Inflamação , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Espécies Reativas de Oxigênio/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
The clearance of apoptotic cells is an essential process to maintain homeostasis of immune system, which is regulated by immunoregulatory cytokines such as TGFß. We show here that Extracellular Vesicles (EVs) were highly released from apoptotic cells, and contributed to macrophage production of TGFß in vitro and in vivo. We further elucidated mechanistically that phosphatidylserine in EVs was a key triggering-factor, and transcription factor FOXO3 was a critical mediator for apoptotic EV-induced TGFß in macrophages. Importantly, we found that macrophages pre-exposed to EVs exhibited an anti-inflammatory phenotype. More strikingly, administration of EVs in vivo promotes Tregs differentiation and suppresses Th1 cell response, and ameliorates experimental colitis. Thus, apoptotic-EV-based treatment might be a promising therapeutic approach for human autoimmune disease.
Assuntos
Colite/patologia , Vesículas Extracelulares/metabolismo , Macrófagos/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Apoptose/efeitos da radiação , Colite/terapia , Modelos Animais de Doenças , Vesículas Extracelulares/transplante , Proteína Forkhead Box O3/antagonistas & inibidores , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Raios gama , Proteínas de Homeodomínio/genética , Humanos , Células Jurkat , Macrófagos/citologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilserinas/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timócitos/efeitos da radiação , Fator de Crescimento Transformador beta/genéticaRESUMO
It is unclear how quiescence is enforced in naive T cells, but activation by foreign antigens and self-antigens is allowed, despite the presence of inhibitory signals. We showed that active transforming growth factor ß (TGF-ß) signaling was present in naive T cells, and T cell receptor (TCR) engagement reduced TGF-ß signaling during T cell activation by downregulating TGF-ß type 1 receptor (TßRI) through activation of caspase recruitment domain-containing protein 11 (CARD11) and nuclear factor κB (NF-κB). TGF-ß prevented TCR-mediated TßRI downregulation, but this was abrogated by interleukin-6 (IL-6). Mitigation of TCR-mediated TßRI downregulation through overexpression of TßRI in naive and activated T cells rendered T cells less responsive and suppressed autoimmunity. Naive T cells in autoimmune patients exhibited reduced TßRI expression and increased TCR-driven proliferation compared to healthy subjects. Thus, TCR-mediated regulation of TßRI-TGF-ß signaling acts as a crucial criterion to determine T cell quiescence and activation.
Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Linfócitos T CD4-Positivos/imunologia , Guanilato Ciclase/metabolismo , Ativação Linfocitária/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Fator de Crescimento Transformador beta1/metabolismo , Animais , Autoimunidade/imunologia , Proteínas Adaptadoras de Sinalização CARD/genética , Linhagem Celular , Proliferação de Células , Colite/imunologia , Colite/patologia , Modelos Animais de Doenças , Regulação para Baixo/imunologia , Guanilato Ciclase/genética , Células HEK293 , Humanos , Interleucina-6/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/biossíntese , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/biossínteseRESUMO
Inflammation is essential in the initial development and progression of many cardiovascular diseases involving innate and adaptive immune responses. The role of CD4(+)CD25(+)FOXP3(+) regulatory T (TREG) cells in the modulation of inflammation and immunity has received increasing attention. Given the important role of TREG cells in the induction and maintenance of immune homeostasis and tolerance, dysregulation in the generation or function of TREG cells can trigger abnormal immune responses and lead to pathology. A wealth of evidence from experimental and clinical studies has indicated that TREG cells might have an important role in protecting against cardiovascular disease, in particular atherosclerosis and abdominal aortic aneurysm. In this Review, we provide an overview of the roles of TREG cells in the pathogenesis of a number of cardiovascular diseases, including atherosclerosis, hypertension, ischaemic stroke, abdominal aortic aneurysm, Kawasaki disease, pulmonary arterial hypertension, myocardial infarction and remodelling, postischaemic neovascularization, myocarditis and dilated cardiomyopathy, and heart failure. Although the exact molecular mechanisms underlying the cardioprotective effects of TREG cells are still to be elucidated, targeted therapies with TREG cells might provide a promising and novel future approach to the prevention and treatment of cardiovascular diseases.
Assuntos
Doenças Cardiovasculares/imunologia , Miocárdio/imunologia , Linfócitos T Reguladores/imunologia , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/prevenção & controle , Proliferação de Células , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária , Miocárdio/metabolismo , Fenótipo , Prognóstico , Fatores de Proteção , Fatores de Risco , Transdução de Sinais , Linfócitos T Reguladores/metabolismoRESUMO
The prevalence of large genomics datasets has made the the need to explore this data more important. Large sequencing projects like the 1000 Genomes Project [1], which reconstructed the genomes of 2,504 individuals sampled from 26 populations, have produced over 200TB of publically available data. Meanwhile, existing genomic visualization tools have been unable to scale with the growing amount of larger, more complex data. This difficulty is acute when viewing large regions (over 1 megabase, or 1,000,000 bases of DNA), or when concurrently viewing multiple samples of data. While genomic processing pipelines have shifted towards using distributed computing techniques, such as with ADAM [4], genomic visualization tools have not. In this work we present Mango, a scalable genome browser built on top of ADAM that can run both locally and on a cluster. Mango presents a combination of different optimizations that can be combined in a single application to drive novel genomic visualization techniques over terabytes of genomic data. By building visualization on top of a distributed processing pipeline, we can perform visualization queries over large regions that are not possible with current tools, and decrease the time for viewing large data sets. Mango is part of the Big Data Genomics project at University of California-Berkeley [25] and is published under the Apache 2 license. Mango is available at https://github.com/bigdatagenomics/mango.
RESUMO
CD4(+)CD25(+)Foxp3(+)regulatory T cells (Treg cells) are extremely important in maintaining immune tolerance. Manipulation of Treg cells, especially autoantigen-specific Treg cells is a promising approach for treatments of autoimmune disease since Treg cells may provide the advantage of antigen specificity without overall immune suppression. However, the clinical application of Treg cells has long been limited due to low numbers of Treg cells and the difficulty in identifying their antigen specificity. In this review, we summarize studies that demonstrate regression of autoimmune diseases using Treg cells as therapeutics. We also discuss approaches to generate polyclonal and autoantigen-specific Treg cells in vitro and in vivo. We also discuss our recent study that describes a novel approach of generating autoantigen-specific Treg cells in vivo and restoring immune tolerance by two steps apoptosis-antigen therapy.
Assuntos
Doenças Autoimunes/terapia , Imunoterapia Adotiva , Linfócitos T Reguladores/imunologia , Animais , Apoptose , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Autoimunidade , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Linfócitos T Reguladores/transplanteRESUMO
The molecular mechanisms by which signaling via transforming growth factor-ß (TGF-ß) and interleukin 4 (IL-4) control the differentiation of CD4(+) IL-9-producing helper T cells (TH9 cells) remain incompletely understood. We found here that the DNA-binding inhibitor Id3 regulated TH9 differentiation, as deletion of Id3 increased IL-9 production from CD4(+) T cells. Mechanistically, TGF-ß1 and IL-4 downregulated Id3 expression, and this process required the kinase TAK1. A reduction in Id3 expression enhanced binding of the transcription factors E2A and GATA-3 to the Il9 promoter region, which promoted Il9 transcription. Notably, Id3-mediated control of TH9 differentiation regulated anti-tumor immunity in an experimental melanoma-bearing model in vivo and also in human CD4(+) T cells in vitro. Thus, our study reveals a previously unrecognized TAK1-Id3-E2A-GATA-3 pathway that regulates TH9 differentiation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Proteínas Inibidoras de Diferenciação/imunologia , Interleucina-9/biossíntese , Proteínas de Neoplasias/imunologia , Animais , Diferenciação Celular , Células Cultivadas , Citometria de Fluxo , Humanos , Proteínas Inibidoras de Diferenciação/genética , Interleucina-9/imunologia , Camundongos , Proteínas de Neoplasias/genética , Reação em Cadeia da Polimerase , Transdução de Sinais/imunologiaRESUMO
The mucosal immune system defends against a vast array of pathogens, yet it exhibits limited responses to commensal microorganisms under healthy conditions. The oral-pharyngeal cavity, the gateway for both the gastrointestinal and respiratory tracts, is composed of complex anatomical structures and is constantly challenged by antigens from air and food. The mucosal immune system of the oral-pharyngeal cavity must prevent pathogen entry while maintaining immune homeostasis, which is achieved via a range of mechanisms that are similar or different to those utilized by the gastrointestinal immune system. In this review, we summarize the features of the mucosal immune system, focusing on T cell subsets and their functions. We also discuss our current understanding of the oral-pharyngeal mucosal immune system.
Assuntos
Imunidade nas Mucosas/imunologia , Mucosa Bucal/imunologia , Subpopulações de Linfócitos T/imunologia , Epitélio/imunologia , Humanos , Imunidade Celular , Doenças da Boca/imunologia , Faringe/imunologia , Subpopulações de Linfócitos T/classificaçãoRESUMO
The evolutionally conserved transforming growth factor ß (TGFß) affects multiple cell types in the immune system by either stimulating or inhibiting their differentiation and function. Studies using transgenic mice with ablation of TGFß or its receptor have revealed the biological significance of TGFß signaling in the control of T cells. However, it is now clear that TGFß is more than an immunosuppressive cytokine. Disruption of TGFß signaling pathway also leads to impaired generation of certain T cell populations. Therefore, in the normal physiological state, TGFß actively maintains T cell homeostasis and regulates T cell function. However, in the tumor microenvironment, TGFß creates an immunosuppressive milieu that inhibits antitumor immunity. Here, we review recent advances in our understanding of the roles of TGFß in the regulation of T cells and tumor immunity.
Assuntos
Neoplasias/imunologia , Linfócitos T/citologia , Linfócitos T/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular/imunologia , Células Dendríticas/imunologia , Humanos , Macrófagos/imunologia , Camundongos , Camundongos Transgênicos , Neutrófilos/imunologia , Receptores de Fatores de Crescimento Transformadores beta/genética , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta/genética , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologiaRESUMO
Transforming growth factor-ß (TGF-ß) receptors (TßRs) are essential components for TGF-ß signal transduction in T cells, yet the mechanisms by which the receptors are regulated remain poorly understood. We show here that Poly(ADP-ribose) polymerase-1 (PARP-1) regulates TGF-ß receptor I (TßRI) and II (TßRII) expression in CD4(+) T cells and subsequently affects Smad2/3-mediated TGF-ß signal transduction. Inhibition of PARP-1 led to the upregulation of both TßRI and TßRII, yet the underlying molecular mechanisms were distinct. PARP-1 selectively bound to the promoter of TßRII, whereas the enzymatic activity of PARP-1 was responsible for the inhibition of TßRI expression. Importantly, inhibition of PARP-1 also enhanced expression of TßRs in human CD4(+) T cells. Thus, PARP-1 regulates TßR expression and TGF-ß signaling in T cells.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Poli(ADP-Ribose) Polimerases/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/biossíntese , Transdução de Sinais/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/imunologia , Fator de Crescimento Transformador beta1/imunologia , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Autoimmune disease can be prevented with immunosuppressive agents; however, the effectiveness of these treatments in advanced stage of disease and the fate of pathogenic T cells following such treatments are not clear. In this study we demonstrate that a single dose of in vitro-induced Treg cells (iTreg cells) resulted in the functional repair and restitution of stomach tissue that had been severely damaged in advanced autoimmune gastritis. iTreg cells caused depletion or inactivation of autoreactive naïve T cells that were antigen inexperienced, however, autoreactive effector/memory T cells persisted in treated mice, resulting in residual cellular infiltrates within the repaired stomach tissue. The persisting autoreactive T cells were able to rapidly cause autoimmune disease if iTreg cells were removed. Similar data were obtained from mice treated continuously with corticosteroid, in that there was substantial restitution of the gastric mucosa; however, effector T cells persisted and rapidly caused pathology following drug removal. Therefore, iTreg cells or corticosteroid can suppress pathogenic autoreactive cells in advanced autoimmune disease, reversing tissue damage and improving tissue function. However, the persistence of pathogenic T cells represents a disease risk.
Assuntos
Doenças Autoimunes/patologia , Gastrite/patologia , Imunoterapia Adotiva , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Corticosteroides/farmacologia , Animais , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Comunicação Celular , Modelos Animais de Doenças , Gastrite/imunologia , Gastrite/terapia , Terapia de Imunossupressão , Ativação Linfocitária , Camundongos , Prednisolona/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/transplanteRESUMO
IL-17, produced by a distinct lineage of CD4(+) helper T (Th) cells termed Th17 cells, induces the production of pro-inflammatory cytokines from resident cells and it has been demonstrated that over-expression of IL-17 plays a crucial role in the onset of several auto-immune diseases. Here we examined the role of IL-17 in the pathogenesis of autoimmune gastritis, a disease that was previously believed to be mediated by IFN-γ. Significantly higher levels of IL-17 and IFN-γ were found in the stomachs and stomach-draining lymph nodes of mice with severe autoimmune gastritis. Unlike IL-17, which was produced solely by CD4(+) T cells in gastritic mice, the majority of IFN-γ-producing cells were CD8(+) T cells. However, CD8(+) T cells alone were not able to induce autoimmune gastritis. T cells that were deficient in IL-17 or IFN-γ production were able to induce autoimmune gastritis but to a much lower extent compared with the disease induced by wild-type T cells. These data demonstrate that production of neither IL-17 nor IFN-γ by effector T cells is essential for the initiation of autoimmune gastritis, but suggest that both are required for the disease to progress to the late pathogenic stage that includes significant tissue disruption.
Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Gastrite/imunologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Células Th17/imunologia , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/transplante , Células Cultivadas , Progressão da Doença , Interferon gama/genética , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Células Th17/transplanteRESUMO
Autoimmune gastritis results from the breakdown of T cell tolerance to the gastric H(+)/K(+) ATPase. The gastric H(+)/K(+) ATPase is responsible for the acidification of gastric juice and consists of an α subunit (H/Kα) and a ß subunit (H/Kß). Here we show that CD4(+) T cells from H/Kα-deficient mice (H/Kα(-/-)) are highly pathogenic and autoimmune gastritis can be induced in sublethally irradiated wildtype mice by adoptive transfer of unfractionated CD4(+) T cells from H/Kα(-/-) mice. All recipient mice consistently developed the most severe form of autoimmune gastritis 8 weeks after the transfer, featuring hypertrophy of the gastric mucosa, complete depletion of the parietal and zymogenic cells, and presence of autoantibodies to H(+)/K(+) ATPase in the serum. Furthermore, we demonstrated that the disease significantly affected stomach weight and stomach pH of recipient mice. Depletion of parietal cells in this disease model required the presence of both H/Kα and H/Kß since transfer of H/Kα(-/-) CD4(+) T cells did not result in depletion of parietal cells in H/Kα(-/-) or H/Kß(-/-) recipient mice. The consistency of disease severity, the use of polyclonal T cells and a specific T cell response to the gastric autoantigen make this an ideal disease model for the study of many aspects of organ-specific autoimmunity including prevention and treatment of the disease.