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1.
Front Cell Infect Microbiol ; 13: 1134119, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37091679

RESUMO

Mucosal-associated invariant T (MAIT) cells are protective against tuberculous and non-tuberculous mycobacterial infections with poorly understood mechanisms. Despite an innate-like nature, MAIT cell responses remain heterogeneous in bacterial infections. To comprehensively characterize MAIT activation programs responding to different bacteria, we stimulated MAIT cells with E. coli to compare with Bacillus Calmette-Guérin (BCG), which remains the only licensed vaccine and a feasible tool for investigating anti-mycobacterial immunity in humans. Upon sequencing mRNA from the activated and inactivated CD8+ MAIT cells, results demonstrated the altered MAIT cell gene profiles by each bacterium with upregulated expression of activation markers, transcription factors, cytokines, and cytolytic mediators crucial in anti-mycobacterial responses. Compared with E. coli, BCG altered more MAIT cell genes to enhance cell survival and cytolysis. Flow cytometry analyses similarly displayed a more upregulated protein expression of B-cell lymphoma 2 and T-box transcription factor Eomesodermin in BCG compared to E.coli stimulations. Thus, the transcriptomic program and protein expression of MAIT cells together displayed enhanced pro-survival and cytotoxic programs in response to BCG stimulation, supporting BCG induces cell-mediated effector responses of MAIT cells to fight mycobacterial infections.


Assuntos
Antineoplásicos , Células T Invariantes Associadas à Mucosa , Mycobacterium bovis , Tuberculose , Humanos , Células T Invariantes Associadas à Mucosa/microbiologia , Vacina BCG , Transcriptoma , Escherichia coli/genética
2.
Front Immunol ; 12: 728685, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659215

RESUMO

Mucosal-associated invariant T (MAIT) cells are an innate-like population of T cells that display a TCR Vα7.2+ CD161+ phenotype and are restricted by the nonclassical MHC-related molecule 1 (MR1). Although B cells control MAIT cell development and function, little is known about the mechanisms underlying their interaction(s). Here, we report, for the first time, that during Salmonella enterica serovar Typhi (S. Typhi) infection, HLA-G expression on B cells downregulates IFN-γ production by MAIT cells. In contrast, blocking HLA-G expression on S. Typhi-infected B cells increases IFN-γ production by MAIT cells. After interacting with MAIT cells, kinetic studies show that B cells upregulate HLA-G expression and downregulate the inhibitory HLA-G receptor CD85j on MAIT cells resulting in their loss. These results provide a new role for HLA-G as a negative feedback loop by which B cells control MAIT cell responses to antigens.


Assuntos
Antígenos CD/metabolismo , Linfócitos B/metabolismo , Antígenos HLA-G/metabolismo , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Salmonella typhi/patogenicidade , Febre Tifoide/metabolismo , Adulto , Antígenos CD/genética , Linfócitos B/imunologia , Linfócitos B/microbiologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interferon gama/genética , Interferon gama/metabolismo , Cinética , Receptor B1 de Leucócitos Semelhante a Imunoglobulina/genética , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/microbiologia , Fenótipo , Salmonella typhi/imunologia , Transdução de Sinais , Febre Tifoide/genética , Febre Tifoide/imunologia , Febre Tifoide/microbiologia , Adulto Jovem
3.
Front Immunol ; 12: 626017, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777009

RESUMO

Mucosal associated invariant T (MAIT) cells play a critical role in Helicobacter pylori (H. pylori)-induced gastritis by promoting mucosal inflammation and aggravating mucosal injuries (1, 2). However, the underlying mechanism and key molecules involved are still uncertain. Here we identified OX40, a co-stimulatory molecule mainly expressed on T cells, as a critical regulator to promote proliferation and IL-9 production by MAIT cells and facilitate mucosal inflammation in H. pylori-positive gastritis patients. Serum examination revealed an increased level of IL-9 in gastritis patients. Meanwhile, OX40 expression was increased in mucosal MAIT cells, and its ligand OX40L was also up-regulated in mucosal dendritic cells (DCs) of gastritis patients, compared with healthy controls. Further results demonstrated that activation of the OX40/OX40L pathway promoted IL-9 production by MAIT cells, and MAIT cells displayed a highly-activated phenotype after the cross-linking of OX40 and OX40L. Moreover, the level of IL-9 produced by MAIT cells was positively correlated with inflammatory indexes in the gastric mucosa, suggesting the potential role of IL-9-producing MAIT cells in mucosal inflammation. Taken together, we elucidated that OX40/OX40L axis promoted mucosal MAIT cell proliferation and IL-9 production in H. pylori-induced gastritis, which may provide potential targeting strategies for gastritis treatment.


Assuntos
Mucosa Gástrica/microbiologia , Gastrite/microbiologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/patogenicidade , Interleucina-9/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Ligante OX40/metabolismo , Receptores OX40/metabolismo , Adulto , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Técnicas de Cocultura , Feminino , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Gastrite/imunologia , Gastrite/metabolismo , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/metabolismo , Helicobacter pylori/imunologia , Interações Hospedeiro-Patógeno , Humanos , Imunidade nas Mucosas , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Fenótipo , Transdução de Sinais , Adulto Jovem
4.
Sci Rep ; 10(1): 20778, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247182

RESUMO

Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset important in the early response to bacterial and viral lung pathogens. MAIT cells recognize bacterial small molecule metabolites presented on the Class I-like molecule MR1. As with other Class I and Class II molecules, MR1 can likely sample ligands in the intracellular environment through multiple cellular pathways. Rab6, a small GTPase that regulates a number of endosomal trafficking pathways including retrograde transport to the trans-Golgi network (TGN), is involved in the presentation of ligands from Mycobacterium tuberculosis (Mtb) to MAIT cells. The Rab6-mediated trafficking pathway contains endosomal compartments that share features with the Mtb intracellular compartment. Using inducible expression of MR1, this study demonstrates that Rab6 regulates the recycling of MR1 molecules from the cell surface through endosomal trafficking compartments to the TGN. This Rab6-dependent pool of recycled MR1, which is available for reloading with ligands from bacterial pathogens like Mtb, may be important for early recognition of infected cells by MAIT cells in the lung.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Proteínas rab de Ligação ao GTP/metabolismo , Adulto , Apresentação de Antígeno , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Endossomos/imunologia , Endossomos/metabolismo , Inativação Gênica , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Imunidade Inata , Técnicas In Vitro , Cinética , Ligantes , Antígenos de Histocompatibilidade Menor/genética , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Regiões Promotoras Genéticas , Transporte Proteico , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/imunologia , Rede trans-Golgi/imunologia , Rede trans-Golgi/metabolismo
5.
Front Immunol ; 11: 1773, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32849637

RESUMO

Mucosa-associated invariant T (MAIT) cells are a unique T cell subset that contributes to protective immunity against microbial pathogens, but little is known about the role of chemokines in recruiting MAIT cells to the site of infection. Pulmonary infection with Francisella tularensis live vaccine strain (LVS) stimulates the accrual of large numbers of MAIT cells in the lungs of mice. Using this infection model, we find that MAIT cells are predominantly CXCR6+ but do not require CXCR6 for accumulation in the lungs. However, CXCR6 does contribute to long-term retention of MAIT cells in the airway lumen after clearance of the infection. We also find that MAIT cells are not recruited from secondary lymphoid organs and largely proliferate in situ in the lungs after infection. Nevertheless, the only known ligand for CXCR6, CXCL16, is sufficient to drive MAIT cell accumulation in the lungs in the absence of infection when administered in combination with the MAIT cell antigen 5-OP-RU. Overall, this new data advances the understanding of mechanisms that facilitate MAIT cell accumulation and retention in the lungs.


Assuntos
Quimiocina CXCL16/administração & dosagem , Quimiotaxia de Leucócito/efeitos dos fármacos , Francisella tularensis/patogenicidade , Pulmão/efeitos dos fármacos , Células T Invariantes Associadas à Mucosa/efeitos dos fármacos , Pneumonia Bacteriana/metabolismo , Receptores CXCR6/metabolismo , Administração Intranasal , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CXCL16/metabolismo , Técnicas de Cocultura , Modelos Animais de Doenças , Francisella tularensis/imunologia , Interações Hospedeiro-Patógeno , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/microbiologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/microbiologia , Receptores CXCR6/deficiência , Receptores CXCR6/genética , Ribitol/administração & dosagem , Ribitol/análogos & derivados , Transdução de Sinais , Uracila/administração & dosagem , Uracila/análogos & derivados
6.
Nat Commun ; 11(1): 272, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31937782

RESUMO

Mucosa-associated invariant T (MAIT) cell loss in chronic HIV-1 infection is a significant insult to antimicrobial immune defenses. Here we investigate the response of MAIT cells during acute HIV-1 infection utilizing the RV217 cohort with paired longitudinal pre- and post-infection samples. MAIT cells are activated and expand in blood and mucosa coincident with peak HIV-1 viremia, in a manner associated with emerging microbial translocation. This is followed by a phase with elevated function as viral replication is controlled to a set-point level, and later by their functional decline at the onset of chronic infection. Interestingly, enhanced innate-like pathways and characteristics develop progressively in MAIT cells during infection, in parallel with TCR repertoire alterations. These findings delineate the dynamic MAIT cell response to acute HIV-1 infection, and show how the MAIT compartment initially responds and expands with enhanced function, followed by progressive reprogramming away from TCR-dependent antibacterial responses towards innate-like functionality.


Assuntos
Infecções por HIV/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Viremia/imunologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Coortes , HIV-1/fisiologia , Humanos , Imunidade Inata/genética , Fatores Reguladores de Interferon/genética , Fatores Reguladores de Interferon/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transcriptoma
7.
Commun Biol ; 2: 203, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31231693

RESUMO

Mucosal-associated invariant T (MAIT) cells typically express a TRAV1-2+ semi-invariant TCRα that enables recognition of bacterial, mycobacterial, and fungal riboflavin metabolites presented by MR1. MAIT cells are associated with immune control of bacterial and mycobacterial infections in murine models. Here, we report that a population of pro-inflammatory TRAV1-2+ CD8+ T cells are present in the airways and lungs of healthy individuals and are enriched in bronchoalveolar fluid of patients with active pulmonary tuberculosis (TB). High-throughput T cell receptor analysis reveals oligoclonal expansions of canonical and donor-unique TRAV1-2+ MAIT-consistent TCRα sequences within this population. Some of these cells demonstrate MR1-restricted mycobacterial reactivity and phenotypes suggestive of MAIT cell identity. These findings demonstrate enrichment of TRAV1-2+ CD8+ T cells with MAIT or MAIT-like features in the airways during active TB and suggest a role for these cells in the human pulmonary immune response to Mycobacterium tuberculosis.


Assuntos
Linfócitos T CD8-Positivos/citologia , Células T Invariantes Associadas à Mucosa/imunologia , Tuberculose Pulmonar/imunologia , Animais , Brônquios/microbiologia , Líquido da Lavagem Broncoalveolar , Broncoscopia , Linfócitos T CD8-Positivos/microbiologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Sistema Imunitário , Inflamação , Intestinos/imunologia , Pulmão/imunologia , Pulmão/microbiologia , Camundongos , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/imunologia , Oregon , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , África do Sul , Tuberculose Pulmonar/microbiologia
8.
Tuberculosis (Edinb) ; 116S: S11-S18, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31072689

RESUMO

TB is a catastrophic infectious disease, affecting roughly one third of the world's population. Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize vitamin B metabolites produced by bacteria, possess effector memory phenotype, and express tissue-homing markers driving migration to sites of infection. Previous research in both Mtb and HIV infections has shown that MAIT cells are depleted in the human periphery, possibly migrating to the tissue sites of infection. We investigated this hypothesis using rhesus macaques (RMs) with active TB, latent TB (LTBI), and SIV-coinfection to explore the effects of different disease states on the MAIT cell populations in vivo. Early in infection, we observed that MAIT cells increased in the blood and bronchoalveolar lavage fluid (BAL) of all infected RMs, irrespective of clinical outcome. However, the frequency of MAIT cells rapidly normalized such that they had returned to baseline levels prior to endpoint. Furthermore, following infection, the chemokines expressed on MAIT cells reflected a strong shift towards a Th1 phenotype from a shared Th1/Th17 phenotype. In conclusion, MAIT cells with enhanced Th1 functions migrating to the site of Mtb-infection. The anti-mycobacterial effector functions of MAIT cells, particularly during the early stages of Mtb infection, had been of interest in promoting protective long-term TB immunity. Our research shows, however, that they have relatively short-acting responses in the host.


Assuntos
Movimento Celular , Proliferação de Células , Imunidade nas Mucosas , Tuberculose Latente/microbiologia , Pulmão/microbiologia , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/patogenicidade , Tuberculose Pulmonar/microbiologia , Animais , Coinfecção , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Tuberculose Latente/imunologia , Pulmão/imunologia , Macaca mulatta , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/virologia , Mycobacterium tuberculosis/imunologia , Fenótipo , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus 40 dos Símios/imunologia , Vírus 40 dos Símios/patogenicidade , Células Th1/imunologia , Células Th1/microbiologia , Células Th2/imunologia , Células Th2/microbiologia , Fatores de Tempo , Tuberculose Pulmonar/imunologia
9.
Curr Opin Immunol ; 58: 75-82, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31141764

RESUMO

MAIT cells are an evolutionarily conserved T cell subset recognizing ubiquitous microbial metabolites. Herein, we review recent literature showing that MAIT cells can be divided into type 1 and type 17 subsets, which acquire a tissue resident differentiation program in the thymus and localize in specific tissues. We also discuss the nature and in vivo availability of the different agonist and antagonist MAIT ligands with potential consequences for MAIT cell biology.


Assuntos
Imunidade nas Mucosas/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Timo/imunologia , Animais , Infecções Bacterianas/imunologia , Infecções Bacterianas/microbiologia , Humanos , Ativação Linfocitária/imunologia , Células T Invariantes Associadas à Mucosa/microbiologia , Micoses/imunologia , Micoses/microbiologia , Células T Matadoras Naturais/microbiologia , Subpopulações de Linfócitos T/microbiologia , Timo/microbiologia
10.
Mucosal Immunol ; 11(6): 1591-1605, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30115998

RESUMO

Human mucosal-associated invariant T (MAIT) cell receptors (TCRs) recognize bacterial riboflavin pathway metabolites through the MHC class 1-related molecule MR1. However, it is unclear whether MAIT cells discriminate between many species of the human microbiota. To address this, we developed an in vitro functional assay through human T cells engineered for MAIT-TCRs (eMAIT-TCRs) stimulated by MR1-expressing antigen-presenting cells (APCs). We then screened 47 microbiota-associated bacterial species from different phyla for their eMAIT-TCR stimulatory capacities. Only bacterial species that encoded the riboflavin pathway were stimulatory for MAIT-TCRs. Most species that were high stimulators belonged to Bacteroidetes and Proteobacteria phyla, whereas low/non-stimulator species were primarily Actinobacteria or Firmicutes. Activation of MAIT cells by high- vs low-stimulating bacteria also correlated with the level of riboflavin they secreted or after bacterial infection of macrophages. Remarkably, we found that human T-cell subsets can also present riboflavin metabolites to MAIT cells in a MR1-restricted fashion. This T-T cell-mediated signaling also induced IFNγ, TNF and granzyme B from MAIT cells, albeit at lower level than professional APC. These findings suggest that MAIT cells can discriminate and categorize complex human microbiota through computation of TCR signals depending on antigen load and presenting cells, and fine-tune their functional responses.


Assuntos
Bacteroidetes/imunologia , Macrófagos/imunologia , Microbiota/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Proteobactérias/imunologia , Riboflavina/metabolismo , Apresentação de Antígeno , Antígenos de Bactérias/imunologia , Células Cultivadas , Engenharia Genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Interferon gama/metabolismo , Ativação Linfocitária , Macrófagos/microbiologia , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
11.
Semin Liver Dis ; 38(1): 60-65, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29471566

RESUMO

The broadening field of microbiome research has led to a substantial reappraisal of the gut-liver axis and its role in chronic liver disease. The liver is a central immunologic organ that is continuously exposed to food and microbial-derived antigens from the gastrointestinal tract. Mucosal-associated invariant T (MAIT) cells are enriched in the human liver and can be activated by inflammatory cytokines and microbial antigens. In chronic inflammatory liver disease, MAIT cells are depleted suggesting an impaired MAIT cell-dependent protection against bacterial infections.


Assuntos
Hepatite Crônica/imunologia , Fígado/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Animais , Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Citocinas/imunologia , Citocinas/metabolismo , Microbioma Gastrointestinal , Hepatite Crônica/diagnóstico , Hepatite Crônica/metabolismo , Hepatite Crônica/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Fígado/metabolismo , Fígado/microbiologia , Fígado/patologia , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Células T Invariantes Associadas à Mucosa/patologia , Fenótipo
12.
Nat Commun ; 9(1): 253, 2018 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-29343684

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can detect bacteria-derived metabolites presented on MR1. Here we show, using a controlled infection of humans with live Salmonella enterica serovar Paratyphi A, that MAIT cells are activated during infection, an effect maintained even after antibiotic treatment. At the peak of infection MAIT cell T-cell receptor (TCR)ß clonotypes that are over-represented prior to infection transiently contract. Select MAIT cell TCRß clonotypes that expand after infection have stronger TCR-dependent activation than do contracted clonotypes. Our results demonstrate that host exposure to antigen may drive clonal expansion of MAIT cells with increased functional avidity, suggesting a role for specific vaccination strategies to increase the frequency and potency of MAIT cells to optimize effector function.


Assuntos
Proliferação de Células , Células T Invariantes Associadas à Mucosa/imunologia , Febre Paratifoide/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Salmonella paratyphi A/imunologia , Adolescente , Adulto , Linhagem Celular Tumoral , Células Clonais/imunologia , Células Clonais/metabolismo , Células Clonais/microbiologia , Voluntários Saudáveis , Interações Hospedeiro-Patógeno/imunologia , Humanos , Células Jurkat , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/microbiologia , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Febre Paratifoide/metabolismo , Febre Paratifoide/microbiologia , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Salmonella paratyphi A/fisiologia , Adulto Jovem
13.
PLoS Biol ; 15(7): e2003167, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28742082

RESUMO

The bacterium Staphylococcus aureus is an important cause of the life-threatening condition toxic shock syndrome in humans. Bacterial toxins known as superantigens (SAgs) generate this illness by acting as broad activators of a substantial fraction of all T lymphocytes, bypassing the normally highly stringent T-cell receptor antigen specificity to cause a systemic inflammatory cytokine storm in the host. In a new study, Shaler et al. found that immune cells called mucosa-associated invariant T (MAIT) cells make an unexpectedly large contribution to the SAg response in a largely T-cell receptor-independent, cytokine-driven manner. Subsequent to such activation, the MAIT cells remain unresponsive to stimulation with bacterial antigen. Thus, S. aureus hijacks MAIT cells in the cytokine storm and leaves them functionally impaired. This work provides new insight into the role of MAIT cells in antibacterial immunity and opens new avenues of investigation to understand and possibly treat bacterial toxic shock and sepsis.


Assuntos
Citocinas/metabolismo , Imunidade Celular , Modelos Imunológicos , Células T Invariantes Associadas à Mucosa/imunologia , Staphylococcus aureus/imunologia , Superantígenos/metabolismo , Animais , Anergia Clonal , Humanos , Ativação Linfocitária , Células T Invariantes Associadas à Mucosa/metabolismo , Células T Invariantes Associadas à Mucosa/microbiologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Linfócitos T/microbiologia
14.
Proc Natl Acad Sci U S A ; 114(27): E5434-E5443, 2017 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-28630305

RESUMO

Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Vα7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity, and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR ß-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84, and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin, and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner.


Assuntos
Citocinas/imunologia , Células Matadoras Naturais/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Linfócitos T/imunologia , Candida albicans/metabolismo , Proliferação de Células , Escherichia coli/metabolismo , Humanos , Imunidade Inata , Memória Imunológica , Células Matadoras Naturais/citologia , Células Matadoras Naturais/microbiologia , Células T Invariantes Associadas à Mucosa/citologia , Células T Invariantes Associadas à Mucosa/microbiologia , Subfamília B de Receptores Semelhantes a Lectina de Células NK/imunologia , Filogenia , Proteoma , Riboflavina/química , Linfócitos T/citologia , Linfócitos T/microbiologia
15.
Sci Rep ; 6: 32320, 2016 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-27586092

RESUMO

The functions of MAIT cells at the site of Mycobacterium tuberculosis infection in humans are still largely unknown. In this study, the phenotypes and immune response of MAIT cells from tuberculous pleural effusions and peripheral blood were investigated. MAIT cells in tuberculous pleural effusions had greatly enhanced IFN-γ, IL-17F and granzyme B response compared with those in peripheral blood. The level of IFN-γ response in MAIT cells from tuberculous pleural effusions was inversely correlated with the extent of tuberculosis infection (p = 0.0006). To determine whether cytokines drive the immune responses of MAIT cells at the site of tuberculosis infection, the role of IL-1ß, IL-2, IL-7, IL-12, IL-15 and IL-18 was investigated. Blockade of IL-2, IL-12 or IL-18 led to significantly reduced production of IFN-γ and/or granzyme B in MAIT cells from tuberculous pleural effusions. Majority of IL-2-producing cells (94.50%) in tuberculous pleural effusions had phenotype of CD3(+)CD4(+), and most IL-12p40-producing cells (91.39%) were CD14(+) cells. MAIT cells had significantly elevated expression of γc receptor which correlated with enhanced immune responses of MAIT cells. It is concluded that MAIT cells from tuberculous pleural effusions exhibited highly elevated immune response to Mtb antigens, which are controlled by cytokines produced by innate/adaptive immune cells.


Assuntos
Imunidade Celular , Células T Invariantes Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Derrame Pleural/imunologia , Transdução de Sinais/imunologia , Tuberculose Pleural/imunologia , Adulto , Anticorpos Bloqueadores/farmacologia , Feminino , Regulação da Expressão Gênica , Granzimas/genética , Granzimas/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/genética , Interleucina-12/imunologia , Subunidade p40 da Interleucina-12/genética , Subunidade p40 da Interleucina-12/imunologia , Interleucina-17/genética , Interleucina-17/imunologia , Interleucina-18/antagonistas & inibidores , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-2/antagonistas & inibidores , Interleucina-2/genética , Interleucina-2/imunologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Masculino , Células T Invariantes Associadas à Mucosa/microbiologia , Mycobacterium tuberculosis/patogenicidade , Derrame Pleural/microbiologia , Derrame Pleural/patologia , Cultura Primária de Células , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Tuberculose Pleural/microbiologia , Tuberculose Pleural/patologia
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