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1.
Nat Commun ; 12(1): 1669, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33723257

RESUMO

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Feminino , Granzimas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Receptores CXCR4/metabolismo
2.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33531712

RESUMO

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Assuntos
/imunologia , Interferon-alfa/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Lavagem Broncoalveolar , Estudos de Casos e Controles , Chlorocebus aethiops , Estudos de Coortes , Feminino , França , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , Índice de Gravidade de Doença , Análise de Célula Única , Células Vero , Adulto Jovem
3.
Viruses ; 13(2)2021 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-33546489

RESUMO

Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprises mild courses of disease as well as progression to severe disease, characterised by lung and other organ failure. The immune system is considered to play a crucial role for the pathogenesis of COVID-19, although especially the contribution of innate-like T cells remains poorly understood. Here, we analysed the phenotype and function of mucosal-associated invariant T (MAIT) cells, innate-like T cells with potent antimicrobial effector function, in patients with mild and severe COVID-19 by multicolour flow cytometry. Our data indicate that MAIT cells are highly activated in patients with COVID-19, irrespective of the course of disease, and express high levels of proinflammatory cytokines such as IL-17A and TNFα ex vivo. Of note, expression of the activation marker HLA-DR positively correlated with SAPS II score, a measure of disease severity. Upon MAIT cell-specific in vitro stimulation, MAIT cells however failed to upregulate expression of the cytokines IL-17A and TNFα, as well as cytolytic proteins, that is, granzyme B and perforin. Thus, our data point towards an altered cytokine expression profile alongside an impaired antibacterial and antiviral function of MAIT cells in COVID-19 and thereby contribute to the understanding of COVID-19 immunopathogenesis.


Assuntos
/imunologia , Ativação Linfocitária , Células T Invariáveis Associadas à Mucosa/imunologia , Imunidade Adaptativa , Citocinas/metabolismo , Feminino , Granzimas/metabolismo , Antígenos HLA-DR , Humanos , Interleucina-17/metabolismo , Células Matadoras Naturais/imunologia , Masculino , Células T Invariáveis Associadas à Mucosa/metabolismo , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Fator de Necrose Tumoral alfa/metabolismo
4.
Science ; 371(6528): 521-526, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33510029

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses and can augment early immune responses and contribute to protection. We hypothesized that MAIT cells may have inherent adjuvant activity in vaccine platforms that use replication-incompetent adenovirus vectors. In mice and humans, ChAdOx1 (chimpanzee adenovirus Ox1) immunization robustly activated MAIT cells. Activation required plasmacytoid dendritic cell (pDC)-derived interferon (IFN)-α and monocyte-derived interleukin-18. IFN-α-induced, monocyte-derived tumor necrosis factor was also identified as a key secondary signal. All three cytokines were required in vitro and in vivo. Activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers and MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. Thus, MAIT cells contribute to the immunogenicity of adenovirus vectors, with implications for vaccine design.


Assuntos
Adenoviridae/imunologia , Imunogenicidade da Vacina , Células T Invariáveis Associadas à Mucosa/imunologia , Vacinas Virais/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Vetores Genéticos/imunologia , Humanos , Interferon-alfa/metabolismo , Interleucina-18/metabolismo , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/metabolismo
5.
Mol Immunol ; 130: 154-158, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33358567

RESUMO

Mucosal associated invariant T (MAIT) cells have a recognised innate-like capacity for antibacterial host defence, consequent on the specificity of their T cell receptor (TCR) for small molecule metabolites produced by a range of prokaryotic and fungal species, their effector memory phenotype, and their expression of cytotoxic molecules. However, recent studies have identified at least two other important functions of MAIT cells in antiviral immunity and in tissue homeostasis and repair. Each are related to distinct transcriptional programmes, which are activated differentially according to the specific immune context. Here we discuss these diverse functions, we review the evidence for the newly identified role of MAIT cells in promoting tissue repair, and we discuss emerging data pointing to the future directions of MAIT cell research including roles in cancer, in antiviral immunity and recent studies in the immune response to SARS-CoV-2 infection. Overall these studies have made us aware of the potential for pleiotropic roles of MAIT cells and related cell populations in micee and humans, and have created a simple and attractive new paradigm for regulation in barrier tissues, where antigen and tissue damage are sensed, integrated and interpreted.


Assuntos
Células T Invariáveis Associadas à Mucosa/imunologia , Animais , Infecções Bacterianas/imunologia , Homeostase , Humanos , Células T Invariáveis Associadas à Mucosa/citologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T , Viroses/imunologia
6.
Mol Immunol ; 130: 64-68, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33360378

RESUMO

The monomorphic MHC-class I-like molecule, MR1, presents small metabolites to T cells. MR1 is the restriction element for microbe-reactive mucosal-associated invariant T (MAIT) cells. MAIT cells have limited TCR usage, including a semi-invariant TCR alpha chain and express high levels of CD161 and CD26. In addition to microbial lumazine metabolites, recent studies have demonstrated that MR1 is able to capture a variety of diverse chemical entities including folate-derivatives, a number of drug-like and other synthetic small molecules, and as yet undefined compounds of self-origin. This capacity of MR1 to bind distinct ligands likely accounts for the recent identification of additional, non-canonical, subsets of MR1-restricted T (MR1T) cells. These subsets can be defined based on their ability to recognize diverse microbes as well as their reactivity to non-microbial cell-endogenous ligands, including tumor-associated antigens. Herein, we will discuss our current understanding of MR1T cell diversity in terms of TCR usage, ligand recognition and functional attributes.


Assuntos
Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Especificidade do Receptor de Antígeno de Linfócitos T/fisiologia , Subpopulações de Linfócitos T/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade nas Mucosas/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/fisiologia , Receptores de Antígenos de Linfócitos T alfa-beta
7.
PLoS One ; 15(12): e0244112, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33382729

RESUMO

OBJECTIVES: Mucosal-associated invariant T (MAIT) cells have been shown to contribute in the pathogenesis of various liver diseases, including chronic hepatitis C virus (HCV) infection. This study was aimed at investigating the frequency, phenotype, and function of circulating MAIT cells, as well as their alterations after successful direct-acting antivirals (DAAs) in HCV-infected patients with or without HIV infection. METHODS: A total 85 patients (51 HCV-monoinfection and 34 HCV/HIV-coinfection), who received elbasvir/grazoprevir from a clinical trial and 20 healthy controls were included. MAIT cells in blood were characterized using flow cytometry at baseline and 24 weeks post-treatment. RESULTS: HCV-monoinfected and HCV/HIV-coinfected patients achieved similar sustained virological response rates (SVR24, 94.1% vs. 97.1%). Circulating MAIT cells in the monoinfection and coinfection groups were presented at low frequencies in comparison with healthy controls (median, 1.1% vs. 1.1% vs. 2.4%, P<0.001) and exhibited features of chronic activation and impaired functional capacity. A negative correlation between circulating MAIT cell frequency and liver stiffness assessed by magnetic resonance elastography was observed. Compared with baseline, increased in circulating MAIT cells after successful DAA therapy was mainly detected in HCV-monoinfected patients compared with HCV/HIV-coinfected individuals. Moreover, MAIT cell restoration was predominantly observed among patients with significant fibrosis to cirrhosis (F2-F4). CONCLUSIONS: These data indicated that dysregulation of MAIT cells might play a role in the progression of chronic HCV infection. Partial restoration of MAIT cell frequency and function was observed after successful DAA therapy, particularly in HCV-monoinfected patients.


Assuntos
Antivirais/administração & dosagem , Benzofuranos/administração & dosagem , Hepacivirus/imunologia , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Imidazóis/administração & dosagem , Células T Invariáveis Associadas à Mucosa/imunologia , Quinoxalinas/administração & dosagem , Adulto , Combinação de Medicamentos , Feminino , Hepacivirus/metabolismo , Hepatite C Crônica/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Células T Invariáveis Associadas à Mucosa/metabolismo
8.
Sci Immunol ; 5(51)2020 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-32989174

RESUMO

Severe COVID-19 is characterized by excessive inflammation of the lower airways. The balance of protective versus pathological immune responses in COVID-19 is incompletely understood. Mucosa-associated invariant T (MAIT) cells are antimicrobial T cells that recognize bacterial metabolites, and can also function as innate-like sensors and mediators of antiviral responses. Here, we investigated the MAIT cell compartment in COVID-19 patients with moderate and severe disease, as well as in convalescence. We show profound and preferential decline in MAIT cells in the circulation of patients with active disease paired with strong activation. Furthermore, transcriptomic analyses indicated significant MAIT cell enrichment and pro-inflammatory IL-17A bias in the airways. Unsupervised analysis identified MAIT cell CD69high and CXCR3low immunotypes associated with poor clinical outcome. MAIT cell levels normalized in the convalescent phase, consistent with dynamic recruitment to the tissues and later release back into the circulation when disease is resolved. These findings indicate that MAIT cells are engaged in the immune response against SARS-CoV-2 and suggest their possible involvement in COVID-19 immunopathogenesis.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Células T Invariáveis Associadas à Mucosa/imunologia , Pneumonia Viral/patologia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Infecções por Coronavirus/imunologia , Feminino , Humanos , Imunidade Inata/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Lectinas Tipo C/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Receptores CXCR3/metabolismo , Adulto Jovem
9.
Proc Natl Acad Sci U S A ; 117(40): 24974-24985, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958637

RESUMO

The antigen-presenting molecule MR1 (MHC class I-related protein 1) presents metabolite antigens derived from microbial vitamin B2 synthesis to activate mucosal-associated invariant T (MAIT) cells. Key aspects of this evolutionarily conserved pathway remain uncharacterized, including where MR1 acquires ligands and what accessory proteins assist ligand binding. We answer these questions by using a fluorophore-labeled stable MR1 antigen analog, a conformation-specific MR1 mAb, proteomic analysis, and a genome-wide CRISPR/Cas9 library screen. We show that the endoplasmic reticulum (ER) contains a pool of two unliganded MR1 conformers stabilized via interactions with chaperones tapasin and tapasin-related protein. This pool is the primary source of MR1 molecules for the presentation of exogenous metabolite antigens to MAIT cells. Deletion of these chaperones reduces the ER-resident MR1 pool and hampers antigen presentation and MAIT cell activation. The MR1 antigen-presentation pathway thus co-opts ER chaperones to fulfill its unique ability to present exogenous metabolite antigens captured within the ER.


Assuntos
Retículo Endoplasmático/genética , Antígenos de Histocompatibilidade Classe I/genética , Metaboloma/genética , Antígenos de Histocompatibilidade Menor/genética , Proteômica , Apresentação do Antígeno/genética , Antígenos/genética , Antígenos/imunologia , Sistemas CRISPR-Cas/genética , Humanos , Ligantes , Ativação Linfocitária/genética , Proteínas de Membrana Transportadoras/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Riboflavina/genética
10.
J Exp Med ; 217(12)2020 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-32886755

RESUMO

COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.


Assuntos
Betacoronavirus/genética , Infecções por Coronavirus/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Matadoras Naturais/metabolismo , Fenótipo , Pneumonia Viral/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , /imunologia , Idoso , Antígenos CD/sangue , Antígenos de Diferenciação de Linfócitos T/sangue , Células Cultivadas , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Feminino , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Lectinas Tipo C/sangue , Masculino , Pessoa de Meia-Idade , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Pandemias , Pneumonia Viral/virologia , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença
11.
Proc Natl Acad Sci U S A ; 117(34): 20717-20728, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32788367

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes activated by bacteria that produce vitamin B2 metabolites. Mouse models of infection have demonstrated a role for MAIT cells in antimicrobial defense. However, proposed protective roles of MAIT cells in human infections remain unproven and clinical conditions associated with selective absence of MAIT cells have not been identified. We report that typhoidal and nontyphoidal Salmonella enterica strains activate MAIT cells. However, S. Typhimurium sequence type 313 (ST313) lineage 2 strains, which are responsible for the burden of multidrug-resistant nontyphoidal invasive disease in Africa, escape MAIT cell recognition through overexpression of ribB This bacterial gene encodes the 4-dihydroxy-2-butanone-4-phosphate synthase enzyme of the riboflavin biosynthetic pathway. The MAIT cell-specific phenotype did not extend to other innate lymphocytes. We propose that ribB overexpression is an evolved trait that facilitates evasion from immune recognition by MAIT cells and contributes to the invasive pathogenesis of S. Typhimurium ST313 lineage 2.


Assuntos
Células T Invariáveis Associadas à Mucosa/imunologia , Salmonella typhimurium/genética , Salmonella typhimurium/metabolismo , África ao Sul do Saara , Antibacterianos , Diarreia/microbiologia , Diarreia/mortalidade , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/fisiologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Infecções por Salmonella/imunologia , Salmonella typhimurium/patogenicidade
12.
Crit Rev Immunol ; 40(2): 173-184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32749095

RESUMO

Mucosa-associated invariant T cells (MAIT cells) are unconventional, innate-like T lymphocytes with remarkable effector and immunoregulatory functions. They are abundant in the human peripheral blood and also enriched in mucosal layers and in the lungs, SARS-CoV-2's main ports of entry. Once activated, MAIT cells produce inflammatory cytokines and cytolytic effector molecules quickly and copiously. MAIT cells are best known for their antibacterial and antifungal properties. However, they are also activated during viral infections, typically in a cytokine-dependent manner, which may promote antiviral immunity. On the other hand, it is plausible to assume active roles for MAIT cells in infection-provoked cytokine storms and tissue damage. SARS-CoV-2 infection may be asymptomatic, mild, severe, or even fatal, depending on sex, age, the presence of preexisting morbidities, and the individual's immunological competence, or lack thereof, among other factors. Based on the available literature, I propose that MAIT cells regulate the host response to SARS-CoV-2 and constitute attractive targets in the prevention or clinical management of coronavirus disease 19 (COVID-19) and some of its complications. Unlike mainstream T cells, MAIT cells are restricted by a monomorphic antigen-presenting molecule called MHC-related protein 1 (MR1). Therefore, MR1 ligands should modify MAIT cell functions relatively uniformly in genetically diverse subjects and may be tested as immunotherapeutic agents or vaccine adjuvants in future studies.


Assuntos
Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariáveis Associadas à Mucosa/imunologia , Pneumonia Viral/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Infecções por Coronavirus/patologia , Citocinas/imunologia , Humanos , Células T Invariáveis Associadas à Mucosa/metabolismo , Pandemias , Pneumonia Viral/patologia
13.
PLoS Biol ; 18(6): e3000644, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511236

RESUMO

Mucosa-associated invariant T (MAIT) cells are abundant antimicrobial T cells in humans and recognize antigens derived from the microbial riboflavin biosynthetic pathway presented by the MHC-Ib-related protein (MR1). However, the mechanisms responsible for MAIT cell antimicrobial activity are not fully understood, and the efficacy of these mechanisms against antibiotic resistant bacteria has not been explored. Here, we show that MAIT cells mediate MR1-restricted antimicrobial activity against Escherichia coli clinical strains in a manner dependent on the activity of cytolytic proteins but independent of production of pro-inflammatory cytokines or induction of apoptosis in infected cells. The combined action of the pore-forming antimicrobial protein granulysin and the serine protease granzyme B released in response to T cell receptor (TCR)-mediated recognition of MR1-presented antigen is essential to mediate control against both cell-associated and free-living, extracellular forms of E. coli. Furthermore, MAIT cell-mediated bacterial control extends to multidrug-resistant E. coli primary clinical isolates additionally resistant to carbapenems, a class of last resort antibiotics. Notably, high levels of granulysin and granzyme B in the MAIT cell secretomes directly damage bacterial cells by increasing their permeability, rendering initially resistant E. coli susceptible to the bactericidal activity of carbapenems. These findings define the role of cytolytic effector proteins in MAIT cell-mediated antimicrobial activity and indicate that granulysin and granzyme B synergize to restore carbapenem bactericidal activity and overcome carbapenem resistance in E. coli.


Assuntos
Antígenos de Diferenciação de Linfócitos T/metabolismo , Carbapenêmicos/farmacologia , Citotoxicidade Imunológica , Farmacorresistência Bacteriana/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Granzimas/metabolismo , Células T Invariáveis Associadas à Mucosa/imunologia , Anti-Infecciosos/farmacologia , Carga Bacteriana/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Células HeLa , Humanos , Cinética
14.
PLoS Pathog ; 16(5): e1008585, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433713

RESUMO

Mucosal-associated invariant T (MAIT) cells can recognize and respond to some bacterially infected cells. Several in vitro and in vivo models of Mycobacterium tuberculosis (Mtb) infection suggest that MAIT cells can contribute to control of Mtb, but these studies are often cross-sectional and use peripheral blood cells. Whether MAIT cells are recruited to Mtb-affected granulomas and lymph nodes (LNs) during early Mtb infection and what purpose they might serve there is less well understood. Furthermore, whether HIV/SIV infection impairs MAIT cell frequency or function at the sites of Mtb replication has not been determined. Using Mauritian cynomolgus macaques (MCM), we phenotyped MAIT cells in the peripheral blood and bronchoalveolar lavage (BAL) before and during infection with SIVmac239. To test the hypothesis that SIV co-infection impairs MAIT cell frequency and function within granulomas, SIV+ and -naïve MCM were infected with a low dose of Mtb Erdman, and necropsied at 6 weeks post Mtb-challenge. MAIT cell frequency and function were examined within the peripheral blood, BAL, and Mtb-affected lymph nodes (LN) and granulomas. MAIT cells did not express markers indicative of T cell activation in response to Mtb in vivo within granulomas in animals infected with Mtb alone. SIV and Mtb co-infection led to increased expression of the activation/exhaustion markers PD-1 and TIGIT, and decreased ability to secrete TNFα when compared to SIV-naïve MCM. Our study provides evidence that SIV infection does not prohibit the recruitment of MAIT cells to sites of Mtb infection, but does functionally impair those MAIT cells. Their impaired function could have impacts, either direct or indirect, on the long-term containment of TB disease.


Assuntos
Coinfecção/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Mycobacterium tuberculosis/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Tuberculose Pulmonar/imunologia , Animais , Coinfecção/patologia , Granuloma/imunologia , Granuloma/patologia , Linfonodos/imunologia , Linfonodos/patologia , Macaca fascicularis , Células T Invariáveis Associadas à Mucosa/patologia , Receptor de Morte Celular Programada 1/imunologia , Receptores Imunológicos/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/patologia , Tuberculose Pulmonar/patologia
15.
Sci Adv ; 6(8): eaaz0374, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128419

RESUMO

Mucosal-associated invariant T (MAIT) cells in HIV-1-infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1-infected subjects were highly activated with the up-regulation of interferon (IFN)-stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti-Mycobacterium tuberculosis responses of MAIT cells from HIV-1-infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti-IFN-I/IL-10 strategies against bacterial coinfections in HIV-1-infected patients.


Assuntos
Infecções por HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , Interferon Tipo I/metabolismo , Interleucina-10/biossíntese , Células T Invariáveis Associadas à Mucosa/imunologia , Células T Invariáveis Associadas à Mucosa/metabolismo , Células T Invariáveis Associadas à Mucosa/virologia , Terapia Antirretroviral de Alta Atividade , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Citocinas/metabolismo , Escherichia coli/imunologia , Infecções por Escherichia coli/etiologia , Feminino , Infecções por HIV/complicações , HIV-1/imunologia , Interações Hospedeiro-Patógeno/imunologia , Humanos , Ativação Linfocitária , Masculino , Transdução de Sinais
16.
Nat Immunol ; 21(4): 400-411, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32123373

RESUMO

Mucosal-associated invariant T (MAIT) cells are activated by microbial riboflavin-based metabolite antigens when presented by MR1. How modifications to the potent antigen 5-OP-RU affect presentation by MR1 and MAIT cell activation remains unclear. Here we design 20 derivatives, termed altered metabolite ligands (AMLs), to dissect the impact of different antigen components on the human MAIT-MR1 axis. Analysis of 11 crystal structures of MAIT T cell antigen receptor (TCR)-MR1-AML ternary complexes, along with biochemical and functional assays, shows that MR1 cell-surface upregulation is influenced by ribityl and non-ribityl components of the ligand and the hydrophobicity of the MR1-AML interface. The polar ribityl chain of the AML strongly influences MAIT cell activation potency through dynamic compensatory interactions within a MAIT TCR-MR1-AML interaction triad. We define the basis by which the MAIT TCR can differentially recognize AMLs, thereby providing insight into MAIT cell antigen specificity and potency.


Assuntos
Antígenos/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Linhagem Celular Tumoral , Humanos , Células Jurkat , Ligantes , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Riboflavina/imunologia
17.
Adv Exp Med Biol ; 1224: 63-77, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32036605

RESUMO

Mucosal-associated invariant T (MAIT) cells are innate T lymphocytes that circulate in blood and also reside in mucosal tissues. Blood MAIT cells are typically highly Th1-polarized, while those in mucosal tissues include both Th1- and Th17-polarized subsets. MAIT cells mount cytokine and cytolytic responses as a result of T cell receptor (TCR)-mediated recognition of microbially derived metabolites of riboflavin (vitamin B2) presented by the MR1 antigen-presenting molecule. Additionally, MAIT cells can be activated by inflammatory cytokines produced by antigen-presenting cells (APCs) that have been exposed to pathogen-associated molecular patterns (PAMPs). Since the antigenic metabolites of riboflavin recognized by MAIT cells are produced by many microorganisms, including pathogens as well as non-pathogenic colonists, the inflammatory state of the tissue may be a key feature that determines the nature of MAIT cell responses. Under normal conditions where inflammatory cytokines are not produced, MAIT cell responses to microbial metabolites may simply serve to help maintain a healthy balance between epithelial cells and microbial colonists. In contrast, in situations where inflammatory cytokines are produced (e.g., pathogenic infection or damage to epithelial tissue), MAIT cell responses may be more potently pro-inflammatory. Since chronic inflammation and microbial drivers are associated with tumorigenesis and also trigger MAIT cell responses, the nexus of MAIT cells, local microbiomes, and epithelial cells may play an important role in epithelial carcinogenesis. This chapter reviews current information about MAIT cells and epithelial tumors, where the balance of evidence suggests that enrichment of Th17-polarized MAIT cells at tumor sites associates with poor patient prognosis. Studying the role of MAIT cells and their interactions with resident microbes offers a novel view of the biology of epithelial tumor progression and may ultimately lead to new approaches to target MAIT cells clinically.


Assuntos
Células Epiteliais/patologia , Células T Invariáveis Associadas à Mucosa , Neoplasias/patologia , Citocinas/imunologia , Humanos , Células T Invariáveis Associadas à Mucosa/efeitos dos fármacos , Células T Invariáveis Associadas à Mucosa/imunologia , Neoplasias/tratamento farmacológico , Prognóstico , Receptores de Antígenos de Linfócitos T/imunologia
18.
J Immunol ; 204(6): 1462-1473, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-32041784

RESUMO

Mucosal-associated invariant T (MAIT) cells are a type of innate lymphocyte and recognize riboflavin (vitamin B2) synthesis products presented by MHC-related protein 1. We investigated long-term reconstitution of MAIT cells and its association with chronic graft-versus-host disease (cGVHD) in a cross-sectional cohort of 173 adult patients after allogeneic hematopoietic cell transplantation. According to donor source, the number of MAIT cells significantly correlated with time after cord blood transplantation (CBT) but not with time after bone marrow transplantation or peripheral blood stem cell transplantation. The number of MAIT cells was significantly lower in patients with cGVHD compared with patients without cGVHD. We also examined the association between MAIT cell reconstitution and gut microbiota as evaluated by 16S ribosomal sequencing of stool samples 1 mo post-CBT in 27 adult patients undergoing CBT. The diversity of gut microbiota was positively correlated with better MAIT cell reconstitution after CBT. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis indicated that amounts of ribB and ribA genes were significantly higher in the microbiomes of patients with subsequent MAIT cell reconstitution after CBT. In conclusion, long-term MAIT cell reconstitution is dependent on the type of donor source. Our data also unveiled an important role for the interaction of circulating MAIT cells with gut microbiota in humans.


Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Microbioma Gastrointestinal/fisiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células T Invariáveis Associadas à Mucosa/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bactérias/genética , Bactérias/isolamento & purificação , Bactérias/metabolismo , Vias Biossintéticas/imunologia , Estudos Transversais , DNA Bacteriano/isolamento & purificação , Fezes/microbiologia , Feminino , Doença Enxerto-Hospedeiro/sangue , Voluntários Saudáveis , Doenças Hematológicas/terapia , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , RNA Ribossômico 16S/genética , Estudos Retrospectivos , Riboflavina/biossíntese , Transplante Homólogo/efeitos adversos , Adulto Jovem
19.
Clin Exp Immunol ; 200(2): 199-213, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32012235

RESUMO

Bile acids (BAs) are produced by liver hepatocytes and were recently shown to exert functions additional to their well-known role in lipid digestion. As yet it is not known whether the mucosal-associated invariant T (MAIT) cells, which represent 10-15% of the hepatic T cell population, are affected by BAs. The focus of the present investigation was on the association of BA serum concentration with MAIT cell function and inflammatory parameters as well as on the relationship of these parameters to body weight. Blood samples from 41 normal weight and 41 overweight children of the Lifestyle Immune System Allergy (LISA) study were analyzed with respect to MAIT cell surface and activation markers [CD107a, CD137, CD69, interferon (IFN)-γ, tumor necrosis factor (TNF)-α] after Escherichia coli stimulation, mRNA expression of promyelocytic leukemia zinc finger protein (PLZF) and major histocompatibility complex class I-related gene protein (MR1), the inflammatory markers C-reactive protein (CRP), interleukin (IL)-8 and macrophage inflammatory protein (MIP)-1α as well as the concentrations of 13 conjugated and unconjugated BAs. Higher body weight was associated with reduced MAIT cell activation and expression of natural killer cell marker (NKp80) and chemokine receptor (CXCR3). BA concentrations were positively associated with the inflammatory parameters CRP, IL-8 and MIP-1α, but were negatively associated with the number of activated MAIT cells and the MAIT cell transcription factor PLZF. These relationships were exclusively found with conjugated BAs. BA-mediated inhibition of MAIT cell activation was confirmed in vitro. Thus, conjugated BAs have the capacity to modulate the balance between pro- and anti-inflammatory immune responses.


Assuntos
Antígenos de Diferenciação/imunologia , Ácidos e Sais Biliares/imunologia , Peso Corporal , Citocinas/imunologia , Ativação Linfocitária , Células T Invariáveis Associadas à Mucosa/imunologia , Adolescente , Feminino , Humanos , Masculino , Células T Invariáveis Associadas à Mucosa/citologia
20.
Immunohorizons ; 4(1): 14-22, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31974109

RESUMO

Mucosal-associated invariant T (MAIT) cells acquire effector function in response to proinflammatory signals, which synergize with TCR-mediated signals. We asked if cell-intrinsic regulatory mechanisms exist to curtail MAIT cell effector function akin to the activation-induced expression of inhibitory receptors by conventional T cells. We examined human MAIT cells from blood and oral mucosal tissues by RNA sequencing and found differential expression of immunoregulatory genes, including CTLA-4, by MAIT cells isolated from tissue. Using an ex vivo experimental setup, we demonstrate that inflammatory cytokines were sufficient to induce CTLA-4 expression on the MAIT cell surface in the absence of TCR signals. Even brief exposure to the cytokines IL-12, IL-15, and IL-18 was sufficient for sustained CTLA-4 expression by MAIT cells. These data suggest that control of CTLA-4 expression is fundamentally different between MAIT cells and conventional T cells. We propose that this mechanism serves to limit MAIT cell-mediated tissue damage.


Assuntos
Antígenos de Superfície/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígeno CTLA-4/imunologia , Citocinas/imunologia , Células T Invariáveis Associadas à Mucosa/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sangue/imunologia , Feminino , Expressão Gênica/imunologia , Humanos , Inflamação/genética , Masculino , Pessoa de Meia-Idade , Membrana Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/imunologia
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