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2.
JCI Insight ; 52019 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-31021819

RESUMO

Bi-allelic inactivating mutations in DOCK8 cause a combined immunodeficiency characterised by severe pathogen infections, eczema, allergies, malignancy and impaired humoral responses. These clinical features result from functional defects in most lymphocyte lineages. Thus, DOCK8 plays a key role in immune cell function. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. While previous reports have described clinical outcomes for DOCK8 deficiency following HSCT, the effect on lymphocyte reconstitution and function has not been investigated. Our study determined whether defects in lymphocyte differentiation and function in DOCK8-deficient patients were restored following HSCT. DOCK8-deficient T and B lymphocytes exhibited aberrant activation and effector function in vivo and in vitro. Frequencies of αß T and MAIT cells were reduced while γδT cells were increased in DOCK8-deficient patients. HSCT improved, abnormal lymphocyte function in DOCK8-deficient patients. Elevated total and allergen-specific IgE in DOCK8-deficient patients decreased over time following HSCT. Our results document the extensive catalogue of cellular defects in DOCK8-deficient patients, and the efficacy of HSCT to correct these defects, concurrent with improvements in clinical phenotypes. Overall, our findings provide mechanisms at a functional cellular level for improvements in clinical features of DOCK8 deficiency post-HSCT, identify biomarkers that correlate with improved clinical outcomes, and inform the general dynamics of immune reconstitution in patients with monogenic immune disorders following HSCT.

3.
Blood ; 134(1): 30-43, 2019 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-31023703

RESUMO

The era of targeted therapies has seen significant improvements in depth of response, progression-free survival, and overall survival for patients with multiple myeloma. Despite these improvements in clinical outcome, patients inevitably relapse and require further treatment. Drug-resistant dormant myeloma cells that reside in specific niches within the skeleton are considered a basis of disease relapse but remain elusive and difficult to study. Here, we developed a method to sequence the transcriptome of individual dormant myeloma cells from the bones of tumor-bearing mice. Our analyses show that dormant myeloma cells express a distinct transcriptome signature enriched for immune genes and, unexpectedly, genes associated with myeloid cell differentiation. These genes were switched on by coculture with osteoblastic cells. Targeting AXL, a gene highly expressed by dormant cells, using small-molecule inhibitors released cells from dormancy and promoted their proliferation. Analysis of the expression of AXL and coregulated genes in human cohorts showed that healthy human controls and patients with monoclonal gammopathy of uncertain significance expressed higher levels of the dormancy signature genes than patients with multiple myeloma. Furthermore, in patients with multiple myeloma, the expression of this myeloid transcriptome signature translated into a twofold increase in overall survival, indicating that this dormancy signature may be a marker of disease progression. Thus, engagement of myeloma cells with the osteoblastic niche induces expression of a suite of myeloid genes that predicts disease progression and that comprises potential drug targets to eradicate dormant myeloma cells.


Assuntos
Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Recidiva Local de Neoplasia/genética , Células-Tronco Neoplásicas/patologia , Nicho de Células-Tronco/genética , Animais , Humanos , Camundongos , Recidiva Local de Neoplasia/patologia , Proteínas Proto-Oncogênicas/genética , Receptores Proteína Tirosina Quinases/genética , Transcriptoma
5.
Trends Immunol ; 40(1): 35-48, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30502023

RESUMO

Subcapsular sinus (SCS) macrophages are strategically positioned at the lymph-tissue interface in the lymph node to trap and present antigen to B cells. Recent murine data has shown that SCS macrophages also prevent the systemic spread of lymph-borne pathogens and are capable of activating a diverse range of innate effector and adaptive memory cells, including follicular memory T cells and memory B cells (Bmems), that are either pre-positioned or rapidly recruited to the subcapsular niche following infection and inflammation. Furthermore, Bmems are rapidly reactivated to differentiate into plasma cells in subcapsular proliferative foci (SPF). Thus, understanding how SCS macrophages coordinate both innate and adaptive memory responses in the subcapsular niche can provide new opportunities to bolster immunity against pathogens and cancer.


Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Linfonodos/imunologia , Macrófagos/imunologia , Animais , Camundongos
6.
Nat Commun ; 9(1): 3372, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30135429

RESUMO

Vaccine-induced immunity depends on the generation of memory B cells (MBC). However, where and how MBCs are reactivated to make neutralising antibodies remain unknown. Here we show that MBCs are prepositioned in a subcapsular niche in lymph nodes where, upon reactivation by antigen, they rapidly proliferate and differentiate into antibody-secreting plasma cells in the subcapsular proliferative foci (SPF). This novel structure is enriched for signals provided by T follicular helper cells and antigen-presenting subcapsular sinus macrophages. Compared with contemporaneous secondary germinal centres, SPF have distinct single-cell molecular signature, cell migration pattern and plasma cell output. Moreover, SPF are found both in human and mouse lymph nodes, suggesting that they are conserved throughout mammalian evolution. Our data thus reveal that SPF is a seat of immunological memory that may be exploited to rapidly mobilise secondary antibody responses and improve vaccine efficacy.


Assuntos
Linfócitos B/metabolismo , Linfonodos/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Humanos , Linfonodos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Modelos Teóricos , Pirazóis/farmacologia , Pirimidinas/farmacologia , Tamoxifeno/farmacologia
7.
Nat Immunol ; 19(8): 791-793, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29988092
8.
Front Immunol ; 9: 1553, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30022984

RESUMO

Single-cell RNA sequencing (scRNA-Seq) is transforming our ability to characterize cells, particularly rare cells that are often overlooked in bulk population analytical approaches. This has lead to the discovery of new cell types and cellular states that echo the underlying heterogeneity and plasticity in the immune system. Technologies for the capture, sequencing, and bioinformatic analysis of single cells are rapidly improving, and scRNA-Seq is now becoming much more accessible to non-specialized laboratories. Here, we describe our experiences in adopting scRNA-Seq to the study of rare immune cells in their microanatomical niches.

9.
J Exp Med ; 215(8): 2073-2095, 2018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30018075

RESUMO

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.


Assuntos
Linfócitos B/citologia , Linfócitos B/imunologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Mutação em Linhagem Germinativa/genética , Fosfatidilinositol 3-Quinases/genética , Animais , Afinidade de Anticorpos/imunologia , Células da Medula Óssea/citologia , Diferenciação Celular , Proliferação de Células , Criança , Mutação com Ganho de Função/genética , Humanos , Switching de Imunoglobulina , Imunoglobulinas/metabolismo , Interleucinas/farmacologia , Camundongos , Modelos Animais , Fenótipo , Fosfatidilinositol 3-Quinases/metabolismo , Plasmócitos/metabolismo , Transdução de Sinais
10.
Elife ; 72018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29985127

RESUMO

Intravital microscopy can provide unique insights into the function of biological processes in a native context. However, physiological motion caused by peristalsis, respiration and the heartbeat can present a significant challenge, particularly for functional readouts such as fluorescence lifetime imaging (FLIM), which require longer acquisition times to obtain a quantitative readout. Here, we present and benchmark Galene, a versatile multi-platform software tool for image-based correction of sample motion blurring in both time resolved and conventional laser scanning fluorescence microscopy data in two and three dimensions. We show that Galene is able to resolve intravital FLIM-FRET images of intra-abdominal organs in murine models and NADH autofluorescence of human dermal tissue imaging subject to a wide range of physiological motions. Thus, Galene can enable FLIM imaging in situations where a stable imaging platform is not always possible and rescue previously discarded quantitative imaging data.


Assuntos
Imagem Tridimensional , Microscopia Intravital , Movimento (Física) , Algoritmos , Animais , Técnicas Biossensoriais , Adesão Celular , Simulação por Computador , Transferência Ressonante de Energia de Fluorescência , Guanosina Trifosfato/metabolismo , Humanos , Intestinos/fisiologia , Camundongos , Microscopia de Fluorescência , Modelos Biológicos , Metástase Neoplásica , Neuropeptídeos/metabolismo , Neoplasias Pancreáticas/patologia , Pele/anatomia & histologia , Software , Proteínas rac1 de Ligação ao GTP/metabolismo , Quinases da Família src/metabolismo
11.
Immunol Rev ; 283(1): 138-149, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29664566

RESUMO

The successful establishment of humoral memory response depends on at least two layers of defense. Pre-existing protective antibodies secreted by long-lived plasma cells act as a first line of defense against reinfection ("constitutive humoral memory"). Previously, a second line of defense in which pathogen-experienced memory B cells are rapidly reactivated to produce antibodies ("reactive humoral memory"), was considered as simply a back-up system for the first line (particularly for re-infection with homologous viruses). However, in the case of re-infection with similar but different strains of viruses, or in response to viral escape mutants, the reactive humoral memory plays a crucial role. Here, we review recent progress in our understanding of how memory B cells are generated in the pre-GC stage and during the GC reaction, and how these memory B cells are robustly reactivated with the help of memory Tfh cells to generate the secondary antibody response. In addition, we discuss how these advances may be relevant to the quest for a vaccine that can induce broadly reactive antibodies against influenza and HIV.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Imunidade Humoral , Memória Imunológica , Ativação Linfocitária/imunologia , Animais , Formação de Anticorpos/imunologia , Humanos , Vacinas/imunologia , Viroses/imunologia , Vírus/imunologia
12.
Annu Rev Immunol ; 36: 339-357, 2018 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-29356584

RESUMO

Maintenance of immunological self-tolerance requires lymphocytes carrying self-reactive antigen receptors to be selectively prevented from mounting destructive or inflammatory effector responses. Classically, self-tolerance is viewed in terms of the removal, editing, or silencing of B and T cells that have formed self-reactive antigen receptors during their early development. However, B cells activated by foreign antigen can enter germinal centers (GCs), where they further modify their antigen receptor by somatic hypermutation (SHM) of their immunoglobulin genes. The inevitable emergence of activated, self-reactive GC B cells presents a unique challenge to the maintenance of self-tolerance that must be rapidly countered to avoid autoantibody production. Here we discuss current knowledge of the mechanisms that enforce B cell self-tolerance, with particular focus on the control of self-reactive GC B cells. We also consider how self-reactive GC B cells can escape self-tolerance to initiate autoantibody production or instead be redeemed via SHM and used in productive antibody responses.


Assuntos
Autoimunidade , Linfócitos B/imunologia , Centro Germinativo/imunologia , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Linfócitos B/metabolismo , Centro Germinativo/metabolismo , Humanos , Tolerância Imunológica , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Plasmócitos/imunologia , Plasmócitos/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
13.
Immunology ; 152(3): 382-387, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28704588

RESUMO

T follicular helper (Tfh) cells have the important function of providing B-cell help for the induction of antigen-specific antibody production. As such, it is important to determine the factors that regulate the development, differentiation and function of Tfh cells. This review highlights some of the recent advances in our understanding of Tfh cell migration, Tfh cell memory and the origins and fate of circulating Tfh cells in the blood, that have been revealed from studies in humans and mice.


Assuntos
Quimiotaxia de Leucócito , Centro Germinativo/imunologia , Infecções por HIV/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Formação de Anticorpos , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular , Centro Germinativo/metabolismo , Centro Germinativo/virologia , Infecções por HIV/sangue , Humanos , Memória Imunológica , Fenótipo , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/virologia
14.
Methods Mol Biol ; 1623: 59-72, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28589347

RESUMO

The germinal center (GC) reaction is the key process for the generation of high affinity antibodies to foreign antigen. Standard experimental techniques such as fluorescence-activated cell sorting and histology have provided numerous insights into the composition and function of the GC. However, these approaches are limited to a "snapshot" in time and are unable to fully capture the dynamic nature of the GC. Intravital two-photon microscopy overcomes these disadvantages and has led to several major advances in the field but is restricted by practical and technical limits that prevent long-range mapping and molecular studies. Here we describe procedures for optical marking or "tagging" of cells in precise microanatomical compartments by two-photon photoconversion that can be used for long-term fate mapping and transcript profiling of GC T and B cells.


Assuntos
Perfilação da Expressão Gênica , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Microscopia , Imagem Molecular , Animais , Biomarcadores , Citometria de Fluxo , Imunofluorescência , Perfilação da Expressão Gênica/métodos , Centro Germinativo/imunologia , Processamento de Imagem Assistida por Computador , Imunização , Linfonodos/citologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Transgênicos , Microscopia/métodos , Imagem Molecular/métodos
15.
Gastroenterology ; 153(3): 723-731.e1, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28601482

RESUMO

BACKGROUND & AIMS: Many patients with inflammatory bowel diseases (IBD) have ongoing bowel symptoms of diarrhea or abdominal pain despite mucosal healing. We investigated whether impaired intestinal permeability contributes to these symptoms. METHODS: We performed a prospective study of intestinal permeability, measured by endoscopic confocal laser endomicroscopy in 110 consecutive subjects (31 with ulcerative colitis [UC], 57 with Crohn's disease [CD], and 22 healthy individuals [controls]) in Sydney, Australia from May 2009 and September 2015. Symptomatic CD was defined by a CD Activity Index score of 150 or more and symptomatic UC by a partial Mayo score of 2 or more. Mucosal healing was defined as CD Endoscopic Index of Severity of 0 in CD or Mayo endoscopic sub-score of 0-1 for patients with UC. Intestinal permeability was quantified by the Confocal Leak Score (CLS; range: 0=no impaired permeability to 100=complete loss of barrier function). The primary endpoint was intestinal permeability in patients with symptomatic IBD in mucosal healing vs patients with asymptomatic IBD in mucosal healing. We determined the sensitivity and specificity of CLS in determining symptoms based on receiver operating characteristic analysis. RESULTS: Ongoing bowel symptoms were present in 16.3% of patients with IBD and mucosal healing (15.4% of patients with CD, 17.4% with UC). Patients with symptomatic IBD had a significantly higher median CLS (19.0) than patients with asymptomatic IBD (7.3; P < .001) or controls (5.9, P < .001). There were no significant differences between patients with IBD in remission vs controls (P = .261). Median CLS was significantly higher in patients with symptomatic than asymptomatic CD (17.7 vs 8.1; P = .009) and patients with symptomatic than asymptomatic UC (22.2 vs 6.9; P = .021). A CLS of 13.1 or more identified ongoing bowel symptoms in patients with IBD and mucosal healing with 95.2% sensitivity and 97.6% specificity; the receiver operating characteristic area under curve value was 0.88. Based on this cutoff, 36.2% of patients with IBD in mucosal healing have increased intestinal permeability. On regression analysis, every increase in CLS of 1.9 correlated with an additional diarrheal motion per day (P = .008). CONCLUSIONS: In a prospective study of intestinal permeability in patients with IBD and mucosal healing, we associated impaired intestinal permeability with ongoing bowel symptoms; increases in permeability correlated with increased severity of diarrhea. Resolution of mucosal permeability beyond mucosal healing might improve outcomes of patients with IDB (ANZCTR.org.au: ACTRN12613001248752).


Assuntos
Colite Ulcerativa/fisiopatologia , Doença de Crohn/fisiopatologia , Mucosa Intestinal/metabolismo , Adulto , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Colite Ulcerativa/diagnóstico por imagem , Colonoscopia , Doença de Crohn/diagnóstico por imagem , Feminino , Humanos , Microscopia Intravital , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Permeabilidade , Estudos Prospectivos , Índice de Gravidade de Doença , Avaliação de Sintomas , Cicatrização
16.
Nat Commun ; 8: 15373, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28497796

RESUMO

Interleukin-2 (IL-2) is an established therapeutic agent used for cancer immunotherapy. Since treatment efficacy is mediated by CD8+ and NK cell activity at the tumour site, considerable efforts have focused on generating variants that expand these subsets systemically, as exemplified by IL-2/antibody complexes and 'superkines'. Here we describe a novel determinant of antitumour activity using fusion proteins consisting of IL-2 and the antibody fragment crystallizable (Fc) region. Generation of long-lived IL-2-Fc variants in which CD25 binding is abolished through mutation effectively prevents unwanted activation of CD25+ regulatory T-cells (Tregs) and results in strong expansion of CD25- cytotoxic subsets. Surprisingly, however, such variants are less effective than wild-type IL-2-Fc in mediating tumour rejection. Instead, we report that efficacy is crucially dependent on depletion of Tregs through Fc-mediated immune effector functions. Our results underpin an unexpected mechanism of action and provide important guidance for the development of next generation IL-2 therapeutics.


Assuntos
Antineoplásicos/farmacologia , Fragmentos de Imunoglobulinas/imunologia , Imunoterapia , Ativação Linfocitária , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos Monoclonais/imunologia , Linfócitos T CD8-Positivos/imunologia , Citocinas/metabolismo , Feminino , Imunoglobulina G/imunologia , Memória Imunológica , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/citologia , Subpopulações de Linfócitos/imunologia , Melanoma Experimental , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutagênese , Neoplasias/terapia , Proteínas Recombinantes/metabolismo , Baço/citologia , Baço/metabolismo
18.
Curr Opin Immunol ; 45: 132-140, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28363157

RESUMO

Immunological memory is a cornerstone of adaptive immune responses in higher vertebrates. The remarkable ability to generate memory cells following Ag exposure, in the context of natural infection or immunization, provides long-lived protection against infectious diseases, often for the hosts' lifetime. Indeed, the generation of memory B cells and long-lived plasma cells underpins the success of most vaccines. The concept of immunological memory is not new-it was first proposed nearly 2500 years ago. While our understanding of the complexities of humoral and cell-mediated memory continues to evolve, important aspects of this process remain unresolved. Here, we will provide an overview of recent advances in B-cell memory in mice and humans, and in health and disease.


Assuntos
Antígenos/imunologia , Memória Imunológica , Plasmócitos/imunologia , Animais , Humanos , Camundongos , Plasmócitos/patologia
19.
J Allergy Clin Immunol ; 139(3): 933-949, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27554822

RESUMO

BACKGROUND: Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency caused by autosomal recessive loss-of-function mutations in DOCK8. This disorder is characterized by recurrent cutaneous infections, increased serum IgE levels, and severe atopic disease, including food-induced anaphylaxis. However, the contribution of defects in CD4+ T cells to disease pathogenesis in these patients has not been thoroughly investigated. OBJECTIVE: We sought to investigate the phenotype and function of DOCK8-deficient CD4+ T cells to determine (1) intrinsic and extrinsic CD4+ T-cell defects and (2) how defects account for the clinical features of DOCK8 deficiency. METHODS: We performed in-depth analysis of the CD4+ T-cell compartment of DOCK8-deficient patients. We enumerated subsets of CD4+ T helper cells and assessed cytokine production and transcription factor expression. Finally, we determined the levels of IgE specific for staple foods and house dust mite allergens in DOCK8-deficient patients and healthy control subjects. RESULTS: DOCK8-deficient memory CD4+ T cells were biased toward a TH2 type, and this was at the expense of TH1 and TH17 cells. In vitro polarization of DOCK8-deficient naive CD4+ T cells revealed the TH2 bias and TH17 defect to be T-cell intrinsic. Examination of allergen-specific IgE revealed plasma IgE from DOCK8-deficient patients is directed against staple food antigens but not house dust mites. CONCLUSION: Investigations into the DOCK8-deficient CD4+ T cells provided an explanation for some of the clinical features of this disorder: the TH2 bias is likely to contribute to atopic disease, whereas defects in TH1 and TH17 cells compromise antiviral and antifungal immunity, respectively, explaining the infectious susceptibility of DOCK8-deficient patients.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/deficiência , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Alérgenos/imunologia , Criança , Pré-Escolar , Citocinas/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Leucócitos Mononucleares/imunologia , Masculino , Adulto Jovem
20.
J Exp Med ; 213(8): 1589-608, 2016 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-27401342

RESUMO

Naive CD4(+) T cells differentiate into specific effector subsets-Th1, Th2, Th17, and T follicular helper (Tfh)-that provide immunity against pathogen infection. The signaling pathways involved in generating these effector cells are partially known. However, the effects of mutations underlying human primary immunodeficiencies on these processes, and how they compromise specific immune responses, remain unresolved. By studying individuals with mutations in key signaling pathways, we identified nonredundant pathways regulating human CD4(+) T cell differentiation in vitro. IL12Rß1/TYK2 and IFN-γR/STAT1 function in a feed-forward loop to induce Th1 cells, whereas IL-21/IL-21R/STAT3 signaling is required for Th17, Tfh, and IL-10-secreting cells. IL12Rß1/TYK2 and NEMO are also required for Th17 induction. Strikingly, gain-of-function STAT1 mutations recapitulated the impact of dominant-negative STAT3 mutations on Tfh and Th17 cells, revealing a putative inhibitory effect of hypermorphic STAT1 over STAT3. These findings provide mechanistic insight into the requirements for human T cell effector function, and explain clinical manifestations of these immunodeficient conditions. Furthermore, they identify molecules that could be targeted to modulate CD4(+) T cell effector function in the settings of infection, vaccination, or immune dysregulation.


Assuntos
Diferenciação Celular/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Antígenos de Diferenciação/genética , Antígenos de Diferenciação/imunologia , Diferenciação Celular/genética , Feminino , Humanos , Interleucina-10/genética , Interleucina-10/imunologia , Masculino , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/imunologia , Células Th1/citologia , Células Th17/citologia
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