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1.
Nature ; 628(8008): 620-629, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38509369

RESUMO

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.


Assuntos
Infecções por Vírus Epstein-Barr , Interleucina-27 , Receptores de Interleucina , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Adulto Jovem , Alelos , Linfócitos B/patologia , Linfócitos B/virologia , Linfócitos T CD8-Positivos/patologia , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/genética , Infecções por Vírus Epstein-Barr/terapia , Finlândia , Frequência do Gene , Herpesvirus Humano 4 , Homozigoto , Mononucleose Infecciosa/complicações , Mononucleose Infecciosa/genética , Mononucleose Infecciosa/terapia , Interleucina-27/imunologia , Interleucina-27/metabolismo , Mutação com Perda de Função , Receptores de Interleucina/deficiência , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Resultado do Tratamento
2.
Mol Cancer ; 21(1): 65, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35246138

RESUMO

BACKGROUND: Anaplastic large cell lymphoma positive for ALK (ALK+ ALCL) is a rare type of non-Hodgkin lymphoma. This lymphoma is caused by chromosomal translocations involving the anaplastic lymphoma kinase gene (ALK). In this study, we aimed to identify mechanisms of transformation and therapeutic targets by generating a model of ALK+ ALCL lymphomagenesis ab initio with the specific NPM-ALK fusion. METHODS: We performed CRISPR/Cas9-mediated genome editing of the NPM-ALK chromosomal translocation in primary human activated T lymphocytes. RESULTS: Both CD4+ and CD8+ NPM-ALK-edited T lymphocytes showed rapid and reproducible competitive advantage in culture and led to in vivo disease development with nodal and extra-nodal features. Murine tumors displayed the phenotypic diversity observed in ALK+ ALCL patients, including CD4+ and CD8+ lymphomas. Assessment of transcriptome data from models and patients revealed global activation of the WNT signaling pathway, including both canonical and non-canonical pathways, during ALK+ ALCL lymphomagenesis. Specifically, we found that the WNT signaling cell surface receptor ROR2 represented a robust and genuine marker of all ALK+ ALCL patient tumor samples. CONCLUSIONS: In this study, ab initio modeling of the ALK+ ALCL chromosomal translocation in mature T lymphocytes enabled the identification of new therapeutic targets. As ROR2 targeting approaches for other cancers are under development (including lung and ovarian tumors), our findings suggest that ALK+ ALCL cases with resistance to current therapies may also benefit from ROR2 targeting strategies.


Assuntos
Linfoma Anaplásico de Células Grandes , Quinase do Linfoma Anaplásico/genética , Animais , Humanos , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Camundongos , Fenótipo , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Translocação Genética
3.
Nat Immunol ; 11(8): 701-8, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20581831

RESUMO

Mucosal-associated invariant T lymphocytes (MAIT lymphocytes) are characterized by two evolutionarily conserved features: an invariant T cell antigen receptor (TCR) alpha-chain and restriction by the major histocompatibility complex (MHC)-related protein MR1. Here we show that MAIT cells were activated by cells infected with various strains of bacteria and yeast, but not cells infected with virus, in both humans and mice. This activation required cognate interaction between the invariant TCR and MR1, which can present a bacteria-derived ligand. In humans, we observed considerably fewer MAIT cells in blood from patients with bacterial infections such as tuberculosis. In the mouse, MAIT cells protected against infection by Mycobacterium abscessus or Escherichia coli. Thus, MAIT cells are evolutionarily conserved innate-like lymphocytes that sense and help fight off microbial infection.


Assuntos
Infecções Bacterianas/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Infecções Bacterianas/microbiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Memória Imunológica , Ativação Linfocitária , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/citologia
4.
J Immunol ; 194(10): 4641-9, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25870247

RESUMO

Mucosal-associated invariant T (MAIT) cells recognize microbial compounds presented by the MHC-related 1 (MR1) protein. Although riboflavin precursor derivatives from Gram-positive bacteria have been characterized, some level of ligand heterogeneity has been suggested through the analysis of the MAIT cell TCR repertoire in humans and differential reactivity of human MAIT cell clones according to the bacteria. In this study, using Gram-negative bacteria mutated for the riboflavin biosynthetic pathway, we show a strict correlation between the ability to synthesize the 5-amino-ribityl-uracil riboflavin precursor and to activate polyclonal and quasi-monoclonal mouse MAIT cells. To our knowledge, we show for the first time that the semipurified bacterial fraction and the synthetic ligand activate murine MAIT cells in vitro and in vivo. We describe new MR1 ligands that do not activate MAIT cells but compete with bacterial and synthetic compounds activating MAIT cells, providing the capacity to modulate MAIT cell activation. Through competition experiments, we show that the most active synthetic MAIT cell ligand displays the same functional avidity for MR1 as does the microbial compound. Altogether, these results show that most, if not all, MAIT cell ligands found in Escherichia coli are related to the riboflavin biosynthetic pathway and display very limited heterogeneity.


Assuntos
Infecções por Escherichia coli/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Riboflavina/imunologia , Riboflavina/metabolismo , Animais , Modelos Animais de Doenças , Escherichia coli/imunologia , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/imunologia , Técnicas In Vitro , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Mucosa/imunologia
5.
PLoS Pathog ; 9(10): e1003681, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24130485

RESUMO

Mucosal associated invariant T cells (MAIT) are innate T lymphocytes that detect a large variety of bacteria and yeasts. This recognition depends on the detection of microbial compounds presented by the evolutionarily conserved major-histocompatibility-complex (MHC) class I molecule, MR1. Here we show that MAIT cells display cytotoxic activity towards MR1 overexpressing non-hematopoietic cells cocultured with bacteria. The NK receptor, CD161, highly expressed by MAIT cells, modulated the cytokine but not the cytotoxic response triggered by bacteria infected cells. MAIT cells are also activated by and kill epithelial cells expressing endogenous levels of MRI after infection with the invasive bacteria Shigella flexneri. In contrast, MAIT cells were not activated by epithelial cells infected by Salmonella enterica Typhimurium. Finally, MAIT cells are activated in human volunteers receiving an attenuated strain of Shigella dysenteriae-1 tested as a potential vaccine. Thus, in humans, MAIT cells are the most abundant T cell subset able to detect and kill bacteria infected cells.


Assuntos
Disenteria Bacilar/imunologia , Imunidade nas Mucosas , Mucosa Intestinal/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Shigella dysenteriae/imunologia , Linfócitos T/imunologia , Disenteria Bacilar/patologia , Células Epiteliais/imunologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Feminino , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Antígenos de Histocompatibilidade Menor , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Infecções por Salmonella/patologia , Linfócitos T/patologia
6.
J Immunol ; 191(12): 6002-9, 2013 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-24244014

RESUMO

NKT and mucosal-associated invariant T (MAIT) cells express semi-invariant TCR and restriction by nonclassical MHC class Ib molecules. Despite common features, the respective development of NKT and MAIT subsets is distinct. NKTs proliferate extensively and acquire effector properties prior to thymic export. MAIT cells exit the thymus as naive cells and acquire an effector/memory phenotype in a process requiring both commensal flora and B cells. During thymic development, NKTs are selected by CD1d-expressing cortical thymocytes; however, the hematopoietic cell type responsible for MAIT cell selection remains unresolved. Using reaggregated thymic organ culture and bone marrow chimeras, we demonstrate that positive selection of mouse iVα19 transgenic and Vß6 transgenic MAIT cell progenitors requires MHC-related 1-expressing CD4(+)CD8(+) double positive thymocytes, whereas thymic B cells, macrophages, and dendritic cell subsets are dispensable. Preincubation of double positive thymocytes with exogenous bacterial ligand increases MHC-related 1 surface expression and enhances mature MAIT cell activation in the in vitro cocultures. The revelation of a common cell type for the selection of both NKT and MAIT subsets raises questions about the mechanisms underlying acquisition of their specific features.


Assuntos
Antígenos CD4/análise , Antígenos CD8/análise , Seleção Clonal Mediada por Antígeno , Antígenos de Histocompatibilidade Classe I/imunologia , Linfopoese/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Antígenos de Bactérias/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Linhagem da Célula , Células Cultivadas , Técnicas de Cocultura , Escherichia coli/imunologia , Feminino , Genes de Imunoglobulinas , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/citologia , Antígenos de Histocompatibilidade Classe I/genética , Região Variável de Imunoglobulina/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/imunologia , Técnicas de Cultura de Órgãos , Quimera por Radiação , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Organismos Livres de Patógenos Específicos , Células Estromais/fisiologia , Subpopulações de Linfócitos T/química , Timo/citologia , Timo/imunologia
7.
Trends Immunol ; 32(5): 212-8, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21459674

RESUMO

Mucosal-associated invariant T (MAIT) cells are a population of T cells that display a semi-invariant T cell receptor (TCR) and are restricted by the evolutionarily conserved major histocompatibility complex related molecule, MR1. Here, we review recent knowledge of this T cell population. MAIT cells are abundant in human blood, gut and liver, and display an effector phenotype. They follow an atypical pathway of development and preferentially locate to peripheral tissues. Human and mouse MAIT cells react to bacterially infected cells in an MR1-dependent manner. They migrate to the infection site and can be protective in experimental infection models. MAIT cells secrete interferon-γ, and interleukin-17 under certain conditions. The species conservation, as well as the wide microbial reactivity, infer an important role for this cell population in immunity.


Assuntos
Infecções Bacterianas/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Mucosa/imunologia , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Interferon gama/metabolismo , Interleucina-17/metabolismo , Ativação Linfocitária , Camundongos , Antígenos de Histocompatibilidade Menor , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/metabolismo
8.
Nat Genet ; 37(7): 692-700, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15924140

RESUMO

Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNgammaR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNgamma. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations ( approximately 1.4%) in 77 genes ( approximately 13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate.


Assuntos
Predisposição Genética para Doença , Leucócitos/metabolismo , Mutação de Sentido Incorreto , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Antibacterianos/farmacologia , Vacina BCG/efeitos adversos , Vacina BCG/farmacologia , Linhagem Celular , Criança , Pré-Escolar , Glicosilação , Humanos , Técnicas In Vitro , Interleucina-12/metabolismo , Leucócitos/efeitos dos fármacos , Leucócitos/microbiologia , Infecções por Mycobacterium/genética , Infecções por Mycobacterium/metabolismo , Tunicamicina/farmacologia
9.
Nat Commun ; 15(1): 1982, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38438357

RESUMO

De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.


Assuntos
Autoimunidade , Desenvolvimento Embrionário , Feminino , Gravidez , Humanos , Animais , Camundongos , Citidina Trifosfato , Autoimunidade/genética , Linfócitos B , Proliferação de Células
10.
Blood ; 117(4): 1250-9, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21084709

RESUMO

Mucosal-associated invariant T (MAIT) cells are very abundant in humans and have antimicrobial specificity, but their functions remain unclear. MAIT cells are CD161(hi)IL-18Rα(+) and either CD4(-)CD8(-) (DN) or CD8αß(int) T cells. We now show that they display an effector-memory phenotype (CD45RA(-)CD45RO(+)CD95(hi)CD62L(lo)), and their chemokine receptor expression pattern (CCR9(int)CCR7(-)CCR5(hi)CXCR6(hi)CCR6(hi)) indicates preferential homing to tissues and particularly the intestine and the liver. MAIT cells can represent up to 45% of the liver lymphocytes. They produce interferon-γ and Granzyme-B as well as high levels of interleukin-17 after phorbol myristate acetate + ionomycin stimulation. Most MAIT cells are noncycling cells (< 1% are Ki-67(+)) and express the multidrug resistance transporter (ABCB1). As expected from this phenotype, MAIT cells are more resistant to chemotherapy than other T-cell populations. These features might also allow MAIT cells to resist the xenobiotics potentially secreted by the gut bacteria. We also show that this population does not appear to have antiviral specificity and that CD8 MAIT cells include almost all the ABCB1(+)CD161(hi) CD8 T cells. Together with their already known abundance and antimicrobial specificity, the gut-liver homing characteristics, high expression of ABCB1, and ability to secrete interleukin-17 probably participate in the antibacterial properties of MAIT cells.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/fisiologia , Resistência a Medicamentos/imunologia , Imunidade nas Mucosas , Interleucina-17/metabolismo , Subfamília B de Receptores Semelhantes a Lectina de Células NK/metabolismo , Xenobióticos/farmacologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/imunologia , Células Cultivadas , Criança , Sangue Fetal/citologia , Sangue Fetal/imunologia , Sangue Fetal/metabolismo , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Imunidade nas Mucosas/imunologia , Recém-Nascido , Subunidade alfa de Receptor de Interleucina-18/metabolismo , Especificidade de Órgãos/imunologia , Receptores de Quimiocinas/metabolismo , Células Th1/imunologia , Células Th1/metabolismo
11.
Life Sci Alliance ; 6(9)2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37348953

RESUMO

The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and CTPS2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells; however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of CTPS1 and/or CTPS2 and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less or not of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.


Assuntos
Carbono-Nitrogênio Ligases , Carbono-Nitrogênio Ligases/genética , Carbono-Nitrogênio Ligases/metabolismo , Uridina Trifosfato/metabolismo , Proliferação de Células , Ciclo Celular , Linhagem Celular
12.
PLoS Biol ; 7(3): e54, 2009 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-19278296

RESUMO

Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)alpha (iTCRalpha) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanValpha7.2 antibody and MAIT cell-specific iTCRalpha and TCRbeta transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRalpha and TCRbeta transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%-4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and gammadelta T cells.


Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade nas Mucosas/imunologia , Células T Matadoras Naturais/fisiologia , Subpopulações de Linfócitos T/fisiologia , Timo/imunologia , Animais , Linfócitos B/fisiologia , Criança , Sangue Fetal/imunologia , Trato Gastrointestinal/citologia , Trato Gastrointestinal/imunologia , Trato Gastrointestinal/microbiologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/imunologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Antígenos de Histocompatibilidade Menor , Proteína com Dedos de Zinco da Leucemia Promielocítica , Receptores de Antígenos de Linfócitos T alfa-beta , Linfócitos T , Timo/citologia
13.
Proc Natl Acad Sci U S A ; 106(20): 8290-5, 2009 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-19416870

RESUMO

Several nonclassical major histocompatibilty antigens (class Ib molecules) have emerged as key players in the early immune response to pathogens or stress. Class Ib molecules activate subsets of T cells that mount effector responses before the adaptive immune system, and thus are called innate T cells. MR1 is a novel class Ib molecule with properties highly suggestive of its regulation of mucosal immunity. The Mr1 gene is evolutionarily conserved, is non-Mhc linked, and controls the development of mucosal-associated invariant T (MAIT) cells. MAIT cells preferentially reside in the gut, and their development is dependent on commensal microbiota. Although these properties suggest that MAIT cells function as innate T cells in the mucosa, this has been difficult to test, due to the (i) paucity of MAIT cells that display MR1-specific activation in vitro and (ii) lack of knowledge of whether or not MR1 presents antigen. Here we show that both mouse and human MAIT cells display a high level of cross-reactivity on mammalian MR1 orthologs, but with differences consistent with limited ligand discrimination. Furthermore, acid eluates from recombinant or cellular MR1 proteins enhance MAIT cell activation in an MR1-specific and cross-species manner. Our findings demonstrate that the presentation pathway of MR1 to MAIT cells is highly evolutionarily conserved.


Assuntos
Apresentação de Antígeno , Evolução Biológica , Antígenos de Histocompatibilidade Classe I/imunologia , Mucosa/imunologia , Linfócitos T/imunologia , Animais , Linhagem Celular , Reações Cruzadas/imunologia , Humanos , Imunidade Inata , Ativação Linfocitária , Subpopulações de Linfócitos , Camundongos , Antígenos de Histocompatibilidade Menor , Dados de Sequência Molecular , Especificidade da Espécie
14.
J Exp Med ; 219(7)2022 07 04.
Artigo em Inglês | MEDLINE | ID: mdl-35657354

RESUMO

Epstein-Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137-CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.


Assuntos
Infecções por Vírus Epstein-Barr , Tumor de Músculo Liso , Ligante 4-1BB , Linfócitos B , Herpesvirus Humano 4 , Humanos , Tumor de Músculo Liso/genética , Tumor de Músculo Liso/metabolismo , Tumor de Músculo Liso/patologia , Linfócitos T
15.
JCI Insight ; 5(5)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32161190

RESUMO

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.


Assuntos
Carbono-Nitrogênio Ligases/genética , Diferenciação Celular , Homozigoto , Linfócitos/imunologia , Mutação , Sistemas CRISPR-Cas , Linhagem Celular , Proliferação de Células , Humanos , Imunofenotipagem , Células Jurkat , Ativação Linfocitária
16.
PLoS Genet ; 2(8): e131, 2006 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-16934001

RESUMO

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)-induced gamma-activating factor-mediated immunity and interferon alpha (IFNA)-induced interferon-stimulated genes factor 3-mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor-mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3-mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding.


Assuntos
Infecções por Mycobacterium/genética , Fator de Transcrição STAT1/genética , Adolescente , Adulto , Alelos , Proteínas de Ciclo Celular/metabolismo , Células Cultivadas , Criança , Pré-Escolar , Análise Mutacional de DNA , Proteínas de Ligação a DNA/metabolismo , Feminino , Proteínas Ligadas por GPI , Regulação da Expressão Gênica , Genes Dominantes , Genes Recessivos , Heterozigoto , Humanos , Imunidade Ativa/genética , Lactente , Fator Gênico 3 Estimulado por Interferon, Subunidade gama/metabolismo , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Modelos Biológicos , Modelos Moleculares , Proteínas Mutantes/química , Mutação , Infecções por Mycobacterium/etiologia , Linhagem , Ligação Proteica , Fator de Transcrição STAT1/metabolismo , Transcrição Gênica , Transfecção/métodos
17.
PLoS Med ; 5(1): e26, 2008 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-18232731

RESUMO

BACKGROUND: Interferon-gamma receptor 1 (IFN-gammaR1) deficiency is a life-threatening inherited disorder, conferring predisposition to mycobacterial diseases. Haematopoietic stem cell transplantation (HSCT) is the only curative treatment available, but is hampered by a very high rate of graft rejection, even with intra-familial HLA-identical transplants. This high rejection rate is not seen in any other congenital disorders and remains unexplained. We studied the underlying mechanism in a mouse model of HSCT for IFN-gammaR1 deficiency. METHODS AND FINDINGS: We demonstrated that HSCT with cells from a syngenic C57BL/6 Ifngr1+/+ donor engrafted well and restored anti-mycobacterial immunity in naive, non-infected C57BL/6 Ifngr1-/- recipients. However, Ifngr1-/- mice previously infected with Mycobacterium bovis bacillus Calmette-Guérin (BCG) rejected HSCT. Like infected IFN-gammaR1-deficient humans, infected Ifngr1-/- mice displayed very high serum IFN-gamma levels before HSCT. The administration of a recombinant IFN-gamma-expressing AAV vector to Ifngr1-/- naive recipients also resulted in HSCT graft rejection. Transplantation was successful in Ifngr1-/- x Ifng-/- double-mutant mice, even after BCG infection. Finally, efficient antibody-mediated IFN-gamma depletion in infected Ifngr1-/- mice in vivo allowed subsequent engraftment. CONCLUSIONS: High serum IFN-gamma concentration is both necessary and sufficient for graft rejection in IFN-gammaR1-deficient mice, inhibiting the development of heterologous, IFN-gammaR1-expressing, haematopoietic cell lineages. These results confirm that IFN-gamma is an anti-haematopoietic cytokine in vivo. They also pave the way for HSCT management in IFN-gammaR1-deficient patients through IFN-gamma depletion from the blood. They further raise the possibility that depleting IFN-gamma may improve engraftment in other settings, such as HSCT from a haplo-identical or unrelated donor.


Assuntos
Transplante de Medula Óssea , Rejeição de Enxerto/fisiopatologia , Interferon gama/fisiologia , Receptores de Interferon/deficiência , Animais , Anticorpos Monoclonais/farmacologia , Dependovirus/genética , Feminino , Predisposição Genética para Doença , Vetores Genéticos/genética , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Células-Tronco Hematopoéticas/metabolismo , Interferon gama/sangue , Interferon gama/deficiência , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/patogenicidade , Quimera por Radiação , Receptores de Interferon/genética , Receptores de Interferon/fisiologia , Proteínas Recombinantes de Fusão/fisiologia , Organismos Livres de Patógenos Específicos , Tuberculose/etiologia , Tuberculose/microbiologia , Receptor de Interferon gama
18.
Infect Immun ; 75(12): 5898-907, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17875636

RESUMO

Mycobacterium abscessus is an emerging rapidly growing mycobacterium that causes tuberculous-like lesions in humans. We studied the immune control of this organism in C57BL/6 mice challenged intravenously with 10(7) CFU. Bacteria were eliminated from both the spleen and the liver within 90 days, and liver histology showed organized granulomatous lesions. A T- and B-cell requirement was investigated by challenging Rag2-/-, Cd3epsilon-/-, and muMT-/- mice. Rag2-/- and Cd3epsilon-/- mice were significantly impaired in the ability to clear M. abscessus from the liver and spleen, and muMT-/- mice were significantly impaired in the ability to clear M. abscessus from the liver, suggesting that infection control was primarily T cell dependent in the spleen and both T and B cell dependent in the liver. The liver granulomatous response was similar to that of wild-type controls in muMT-/- mice but completely absent in Cd3epsilon-/- and Rag2-/- mice. We studied the involvement of gamma interferon (IFN-gamma) and tumor necrosis factor (TNF) by challenging C57BL/6 mice deficient in the IFN-gamma receptor (Ifngr1-/-) and in TNF (Tnf-/-). Ifngr1-/- mice were significantly impaired in M. abscessus control both in the spleen and in the liver, and granulomas were profoundly altered. The effect was even more substantial in Tnf-/- mice; they failed to control M. abscessus infection in the liver and died within 20 to 25 days after infection with many hepatic inflammatory foci and major lesions of ischemic necrosis in the liver and kidney. These features were not observed with the closely related species M. chelonae. T-cell immunity, IFN-gamma, and TNF are central factors for the control of M. abscessus in C57BL/6 mice, as they are for the control of pathogenic slowly growing mycobacteria.


Assuntos
Interferon gama/imunologia , Infecções por Mycobacterium/imunologia , Mycobacterium/imunologia , Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/microbiologia , Modelos Animais de Doenças , Memória Imunológica , Fígado/imunologia , Fígado/microbiologia , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Mycobacterium/crescimento & desenvolvimento , Infecções por Mycobacterium/microbiologia , Baço/imunologia , Baço/microbiologia , Linfócitos T/microbiologia
19.
J Clin Invest ; 114(10): 1512-7, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15546002

RESUMO

We investigated the molecular mechanism underlying a severe combined immunodeficiency characterized by the selective and complete absence of T cells. The condition was found in 5 patients and 2 fetuses from 3 consanguineous families. Linkage analysis performed on the 3 families revealed that the patients were carrying homozygous haplotypes within the 11q23 region, in which the genes encoding the gamma, delta, and epsilon subunits of CD3 are located. Patients and affected fetuses from 2 families were homozygous for a mutation in the CD3D gene, and patients from the third family were homozygous for a mutation in the CD3E gene. The thymus from a CD3delta-deficient fetus was analyzed and revealed that T cell differentiation was blocked at entry into the double positive (CD4+CD8+) stage with the accumulation of intermediate CD4-single positive cells. This indicates that CD3delta plays an essential role in promoting progression of early thymocytes toward double-positive stage. Altogether, these findings extend the known molecular mechanisms underlying severe combined immunodeficiency to a new deficiency, i.e., CD3epsilon deficiency, and emphasize the essential roles played by the CD3epsilon and CD3delta subunits in human thymocyte development, since these subunits associate with both the pre-TCR and the TCR.


Assuntos
Complexo CD3/genética , Complexo Receptor-CD3 de Antígeno de Linfócitos T/genética , Imunodeficiência Combinada Severa/etiologia , Antígenos CD4/imunologia , Antígenos CD8/imunologia , Diferenciação Celular/imunologia , Cromossomos Humanos Par 11 , Consanguinidade , Feminino , Mutação da Fase de Leitura , Ligação Genética , Haplótipos , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Linhagem , Complexo Receptor-CD3 de Antígeno de Linfócitos T/deficiência , Imunodeficiência Combinada Severa/genética , Transdução de Sinais/imunologia , Timo/citologia , Timo/imunologia
20.
J Exp Med ; 214(1): 73-89, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011863

RESUMO

Epstein-Barr virus (EBV) infection in humans is a major trigger of malignant and nonmalignant B cell proliferations. CD27 is a co-stimulatory molecule of T cells, and inherited CD27 deficiency is characterized by high susceptibility to EBV infection, though the underlying pathological mechanisms have not yet been identified. In this study, we report a patient suffering from recurrent EBV-induced B cell proliferations including Hodgkin's lymphoma because of a deficiency in CD70, the ligand of CD27. We show that EBV-specific T lymphocytes did not expand properly when stimulated with CD70-deficient EBV-infected B cells, whereas expression of CD70 in B cells restored expansion, indicating that CD70 on B cells but not on T cells is required for efficient proliferation of T cells. CD70 was found to be up-regulated on B cells when activated and during EBV infection. The proliferation of T cells triggered by CD70-expressing B cells was dependent on CD27 and CD3 on T cells. Importantly, CD27-deficient T cells failed to proliferate when stimulated with CD70-expressing B cells. Thus, the CD70-CD27 pathway appears to be a crucial component of EBV-specific T cell immunity and more generally for the immune surveillance of B cells and may be a target for immunotherapy of B cell malignancies.


Assuntos
Ligante CD27/fisiologia , Infecções por Vírus Epstein-Barr/imunologia , Transdução de Sinais/fisiologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Linfócitos B/imunologia , Ligante CD27/deficiência , Ligante CD27/genética , Criança , Códon sem Sentido , Humanos , Ativação Linfocitária , Masculino , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia
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