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1.
Annu Rev Immunol ; 34: 479-510, 2016 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-26927205

RESUMO

CD1- and MHC-related molecule-1 (MR1)-restricted T lymphocytes recognize nonpeptidic antigens, such as lipids and small metabolites, and account for a major fraction of circulating and tissue-resident T cells. They represent a readily activated, long-lasting population of effector cells and contribute to the early phases of immune response, orchestrating the function of other cells. This review addresses the main aspects of their immunological functions, including antigen and T cell receptor repertoires, mechanisms of nonpeptidic antigen presentation, and the current evidence for their participation in human and experimental diseases.


Assuntos
Doenças Autoimunes/imunologia , Infecções/imunologia , Células Matadoras Naturais/imunologia , Ativação Linfocitária , Células T Matadoras Naturais/fisiologia , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Apresentação de Antígeno , Antígenos/imunologia , Antígenos CD1/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Vigilância Imunológica , Antígenos de Histocompatibilidade Menor/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/genética
3.
Nat Immunol ; 14(9): 908-16, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23872678

RESUMO

Human T cells that express a T cell antigen receptor (TCR) containing γ-chain variable region 9 and δ-chain variable region 2 (Vγ9Vδ2) recognize phosphorylated prenyl metabolites as antigens in the presence of antigen-presenting cells but independently of major histocompatibility complex (MHC), the MHC class I-related molecule MR1 and antigen-presenting CD1 molecules. Here we used genetic approaches to identify the molecule that binds and presents phosphorylated antigens. We found that the butyrophilin BTN3A1 bound phosphorylated antigens with low affinity, at a stoichiometry of 1:1, and stimulated mouse T cells with transgenic expression of a human Vγ9Vδ2 TCR. The structures of the BTN3A1 distal domain in complex with host- or microbe-derived phosphorylated antigens had an immunoglobulin-like fold in which the antigens bound in a shallow pocket. Soluble Vγ9Vδ2 TCR interacted specifically with BTN3A1-antigen complexes. Accordingly, BTN3A1 represents an antigen-presenting molecule required for the activation of Vγ9Vδ2 T cells.


Assuntos
Antígenos CD/metabolismo , Antígenos/imunologia , Antígenos/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD/química , Antígenos CD/genética , Butirofilinas , Cromossomos Humanos Par 6 , Humanos , Camundongos , Camundongos Transgênicos , Modelos Moleculares , Organofosfatos/química , Organofosfatos/metabolismo , Fosforilação , Ligação Proteica , Conformação Proteica , Receptores de Antígenos de Linfócitos T gama-delta/imunologia
4.
Clin Exp Immunol ; 215(1): 79-93, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-37586415

RESUMO

Crohn's disease (CD) is a chronic immune-mediated disorder of the gastrointestinal tract. Extensive screening studies have revealed the accumulation of immune cell subsets with unique plasticity and immunoregulatory properties in patients with CD. We performed phenotypic and functional studies on inflamed and non-inflamed bioptic tissue to investigate the presence of distinct T cells in the intestinal mucosa of CD patients. We analysed hundreds of surface molecules expressed on cells isolated from the intestinal tissue of CD patients using anti-CD45 mAbs-based barcoding. A gene ontology enrichment analysis showed that proteins that regulate the activation of T cells were the most enriched group. We, therefore, designed T-cell focused multicolour flow-cytometry panels and performed clustering analysis which revealed an accumulation of activated TEM CD4+CD39+ T cells producing IL-17 and IL-21 and increased frequency of terminally differentiated TCR Vδ1+ cells producing TNF-α and IFN-γ in inflamed tissue of CD patients. The different functional capacities of CD4+ and TCR Vδ1+ cells in CD lesions indicate their non-overlapping contribution to inflammation. The abnormally high number of terminally differentiated TCR Vδ1+ cells suggests that they are continuously activated in inflamed tissue, making them a potential target for novel therapies.


Assuntos
Doença de Crohn , Humanos , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas de Membrana , Inflamação , Linfócitos T
5.
Nat Immunol ; 13(5): 474-80, 2012 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-22426352

RESUMO

The development and maturation of semi-invariant natural killer T cells (iNKT cells) rely on the recognition of self antigens presented by CD1d restriction molecules in thymus. The nature of the stimulatory thymic self lipids remains elusive. We isolated lipids from thymocytes and found that ether-bonded mono-alkyl glycerophosphates and the precursors and degradation products of plasmalogens stimulated iNKT cells. Synthetic analogs showed high potency in activating thymic and peripheral iNKT cells. Mice deficient in the peroxisomal enzyme glyceronephosphate O-acyltransferase (GNPAT), essential for the synthesis of ether lipids, had significant alteration of the thymic maturation of iNKT cells and fewer iNKT cells in both thymus and peripheral organs, which confirmed the role of ether-bonded lipids as iNKT cell antigens. Thus, peroxisome-derived lipids are nonredundant self antigens required for the generation of a full iNKT cell repertoire.


Assuntos
Lipídeos/imunologia , Células T Matadoras Naturais/imunologia , Peroxissomos/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Antígenos CD/metabolismo , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Interleucina-4/metabolismo , Lectinas Tipo C/metabolismo , Lipídeos/isolamento & purificação , Lisofosfolipídeos/imunologia , Lisofosfolipídeos/metabolismo , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/metabolismo , Peroxissomos/química , Fosfatidiletanolaminas/imunologia , Fosfatidiletanolaminas/metabolismo , Timócitos/citologia , Timócitos/metabolismo , Timo/metabolismo
6.
Immunity ; 40(1): 5-7, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439262

RESUMO

Invariant natural killer T cells are preactivated lymphocytes that react upon recognition of CD1d-antigen complexes. Accordingly, any type of CD1d-positive cell could behave as antigen-presenting cell (APC). In this issue of Immunity, Arora et al. (2014), report that professional APCs still make the difference.


Assuntos
Citocinas/metabolismo , Células Dendríticas/imunologia , Células T Matadoras Naturais/imunologia , Animais
7.
Eur J Immunol ; 47(7): 1171-1180, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28440548

RESUMO

Allergic contact dermatitis is a primarily T-cell-mediated inflammatory skin disease induced by exposure to small molecular-weight haptens, which covalently bind to proteins. The abundance of cutaneous T cells that recognize CD1a antigen-presenting molecules raises the possibility that MHC-independent antigen presentation may be relevant in some hapten-driven immune responses. Here we examine the ability of contact sensitizers to influence CD1-restricted immunity. Exposure of human antigen-presenting cells such as monocyte-derived dendritic cells and THP-1 cells to the prototypical contact sensitizer dinitrochlorobenzene potentiated the response of CD1a- and CD1d-autoreactive T cells, which released a vast array of cytokines in a CD1- and TCR-dependent manner. The potentiating effects of dinitrochlorobenzene depended upon newly synthesized CD1 molecules and the presence of endogenous stimulatory lipids. Further examination of a broad panel of contact sensitizers revealed 1,4-benzoquinone, resorcinol, isoeugenol, and cinnamaldehyde to activate the same type of CD1-restricted responses. These findings provide a basis for the antigen-specific activation of skin-associated CD1-restricted T cells by small molecules and may have implications for contact sensitizer-induced inflammatory skin diseases.


Assuntos
Antígenos CD1/imunologia , Dermatite de Contato/imunologia , Células T Matadoras Naturais/imunologia , Linfócitos T/imunologia , Acroleína/análogos & derivados , Acroleína/farmacologia , Apresentação de Antígeno , Benzoquinonas/farmacologia , Linhagem Celular , Células Dendríticas/imunologia , Dinitroclorobenzeno/farmacologia , Eugenol/análogos & derivados , Eugenol/farmacologia , Humanos , Lipídeos/imunologia , Ativação Linfocitária , Monócitos/efeitos dos fármacos , Resorcinóis/farmacologia , Pele/imunologia
8.
Eur J Immunol ; 46(1): 147-53, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26426881

RESUMO

Globotriaosylceramide (Gb3) is a glycosphingolipid present in cellular membranes that progressively accumulates in Fabry disease. Invariant Natural Killer T (iNKT) cells are a population of lipid-specific T cells that are phenotypically and functionally altered in Fabry disease. The mechanisms responsible for the iNKT-cell alterations in Fabry disease are not well understood. Here, we analyzed the effect of Gb3 on CD1d-mediated iNKT-cell activation in vitro using human cells and in vivo in the mouse model. We found that Gb3 competes with endogenous and exogenous antigens for CD1d binding, thereby reducing the activation of iNKT cells. This effect was exerted by a reduction in the amount of stimulatory CD1d:α-GalCer complexes in the presence of Gb3 as demonstrated by using an mAb specific for the complex. We also found that administration of Gb3 delivered to the same APC as α-GalCer, induces reduced iNKT-cell activation in vivo. This work highlights the complexity of iNKT-cell activation and the importance of nonantigenic glycosphingolipids in the modulation of this process.


Assuntos
Antígenos CD1d/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Triexosilceramidas/imunologia , Animais , Modelos Animais de Doenças , Doença de Fabry/imunologia , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C57BL
9.
Nat Chem Biol ; 10(11): 950-6, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25282505

RESUMO

Severe forms of pneumococcal meningitis, bacteraemia and pneumonia result in more than 1 million deaths each year despite the widespread introduction of carbohydrate-protein conjugate vaccines against Streptococcus pneumoniae. Here we describe a new and highly efficient antipneumococcal vaccine design based on synthetic conjugation of S. pneumoniae capsule polysaccharides to the potent lipid antigen α-galactosylceramide, which stimulates invariant natural killer T (iNKT) cells when presented by the nonpolymorphic antigen-presenting molecule CD1d. Mice injected with the new lipid-carbohydrate conjugate vaccine produced high-affinity IgG antibodies specific for pneumococcal polysaccharides. Vaccination stimulated germinal center formation; accumulation of iNKT cells with a T follicular helper cell phenotype; and increased frequency of carbohydrate-specific, long-lived memory B cells and plasmablasts. This new lipid-carbohydrate vaccination strategy induced potent antipolysaccharide immunity that protected against pneumococcal disease in mice and may also prove effective for the design of carbohydrate-based vaccines against other major bacterial pathogens.


Assuntos
Carboidratos/química , Lipídeos/química , Vacinas Pneumocócicas/síntese química , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Vacinas Sintéticas/química , Vacinas Sintéticas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Linfócitos B/citologia , Linfócitos B/imunologia , Carboidratos/administração & dosagem , Linhagem Celular , Centro Germinativo/citologia , Centro Germinativo/imunologia , Células HL-60 , Humanos , Imunização Passiva , Memória Imunológica/imunologia , Cinética , Lipídeos/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Vacinas Pneumocócicas/administração & dosagem , Vacinas Pneumocócicas/química , Fatores de Tempo , Vacinas Sintéticas/administração & dosagem
10.
Nat Rev Immunol ; 5(6): 485-96, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15928680

RESUMO

Recent studies have shown that the recognition of lipid antigens by the immune system is important for defence against infection and other diseases, and that lipid-specific responses occur at higher frequencies than previously suspected. Thanks to several recent advances in this field, we now have a better appreciation of the molecular and cellular requirements of T-cell stimulation by lipids. These findings have raised new questions about the mechanisms of lipid presentation, the priming and clonal expansion of lipid-specific T cells, and their differentiation into memory cells. A greater understanding of lipid-specific T cells and the molecular mechanisms of lipid immunogenicity should facilitate the development of lipid-based vaccines.


Assuntos
Antígenos de Bactérias/imunologia , Antígenos CD1/imunologia , Autoantígenos/imunologia , Lipídeos/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos de Bactérias/química , Antígenos CD1/metabolismo , Autoantígenos/química , Autoimunidade/imunologia , Transporte Biológico , Humanos , Memória Imunológica , Metabolismo dos Lipídeos , Lipídeos/química , Linfopoese , Linfócitos T/metabolismo
11.
Trends Immunol ; 33(3): 103-11, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22342205

RESUMO

T cells recognizing lipid antigens are present in large numbers in circulating blood. They exert multiple functions including immunoregulation, tumour surveillance and protection during infection. Here, we review the latest information on the mechanisms of lipid antigen presentation by CD1 molecules. Recent studies have provided insight into CD1 trafficking within the cell, lipid distribution and handling, CD1 maturation, lipid antigen processing and loading. The structural resolution of all human CD1 molecules has revealed unique features that correlate with function. Molecular mechanisms regulating CD1 expression and multiple evasion mechanisms evolved by viral and bacterial pathogens have been disclosed. With rapid progression, these studies have decoded lipid-specific immunity and have revealed the important immunological role of this type of antigen recognition.


Assuntos
Apresentação de Antígeno , Lipídeos/imunologia , Animais , Antígenos CD1/química , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Regulação da Expressão Gênica , Humanos , Transporte Proteico
12.
Immunity ; 33(6): 831-3, 2010 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-21168772
13.
Proc Natl Acad Sci U S A ; 108(34): 14228-33, 2011 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-21844346

RESUMO

CD1e is a member of the CD1 family that participates in lipid antigen presentation without interacting with the T-cell receptor. It binds lipids in lysosomes and facilitates processing of complex glycolipids, thus promoting editing of lipid antigens. We find that CD1e may positively or negatively affect lipid presentation by CD1b, CD1c, and CD1d. This effect is caused by the capacity of CD1e to facilitate rapid formation of CD1-lipid complexes, as shown for CD1d, and also to accelerate their turnover. Similar results were obtained with antigen-presenting cells from CD1e transgenic mice in which lipid complexes are assembled more efficiently and show faster turnover than in WT antigen-presenting cells. These effects maximize and temporally narrow CD1-restricted responses, as shown by reactivity to Sphingomonas paucimobilis-derived lipid antigens. CD1e is therefore an important modulator of both group 1 and group 2 CD1-restricted responses influencing the lipid antigen availability as well as the generation and persistence of CD1-lipid complexes.


Assuntos
Antígenos CD1/imunologia , Imunidade/imunologia , Lipídeos/imunologia , Animais , Apresentação de Antígeno/imunologia , Células Clonais , Células Dendríticas/imunologia , Glicolipídeos/imunologia , Glicoproteínas/imunologia , Infecções por Bactérias Gram-Negativas/imunologia , Humanos , Cinética , Camundongos , Camundongos Transgênicos , Células T Matadoras Naturais/imunologia , Sphingomonas/imunologia
14.
Proc Natl Acad Sci U S A ; 108(32): 13230-5, 2011 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-21788486

RESUMO

CD1e is the only human CD1 protein existing in soluble form in the late endosomes of dendritic cells, where it facilitates the processing of glycolipid antigens that are ultimately recognized by CD1b-restricted T cells. The precise function of CD1e remains undefined, thus impeding efforts to predict the participation of this protein in the presentation of other antigens. To gain insight into its function, we determined the crystal structure of recombinant CD1e expressed in human cells at 2.90-Å resolution. The structure revealed a groove less intricate than in other CD1 proteins, with a significantly wider portal characterized by a 2 Å-larger spacing between the α1 and α2 helices. No electron density corresponding to endogenous ligands was detected within the groove, despite the presence of ligands unequivocally established by native mass spectrometry in recombinant CD1e. Our structural data indicate that the water-exposed CD1e groove could ensure the establishment of loose contacts with lipids. In agreement with this possibility, lipid association and dissociation processes were found to be considerably faster with CD1e than with CD1b. Moreover, CD1e was found to mediate in vitro the transfer of lipids to CD1b and the displacement of lipids from stable CD1b-antigen complexes. Altogether, these data support that CD1e could have evolved to mediate lipid-exchange/editing processes with CD1b and point to a pathway whereby the repertoire of lipid antigens presented by human dendritic cells might be expanded.


Assuntos
Antígenos CD1/química , Antígenos CD1/metabolismo , Metabolismo dos Lipídeos , Lipídeos/química , Acilação , Cristalografia por Raios X , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína
15.
Proc Natl Acad Sci U S A ; 108(43): 17755-60, 2011 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-22006319

RESUMO

The mechanisms permitting nonpolymorphic CD1 molecules to present lipid antigens that differ considerably in polar head and aliphatic tails remain elusive. It is also unclear why hydrophobic motifs in the aliphatic tails of some antigens, which presumably embed inside CD1 pockets, contribute to determinants for T-cell recognition. The 1.9-Å crystal structure of an active complex of CD1b and a mycobacterial diacylsulfoglycolipid presented here provides some clues. Upon antigen binding, endogenous spacers of CD1b, which consist of a mixture of diradylglycerols, moved considerably within the lipid-binding groove. Spacer displacement was accompanied by F' pocket closure and an extensive rearrangement of residues exposed to T-cell receptors. Such structural reorganization resulted in reduction of the A' pocket capacity and led to incomplete embedding of the methyl-ramified portion of the phthioceranoyl chain of the antigen, explaining why such hydrophobic motifs are critical for T-cell receptor recognition. Mutagenesis experiments supported the functional importance of the observed structural alterations for T-cell stimulation. Overall, our data delineate a complex molecular mechanism combining spacer repositioning and ligand-induced conformational changes that, together with pocket intricacy, endows CD1b with the required molecular plasticity to present a broad range of structurally diverse antigens.


Assuntos
Antígenos CD1/química , Glicolipídeos/química , Modelos Moleculares , Mycobacterium tuberculosis/química , Conformação Proteica , Antígenos CD1/metabolismo , Cromatografia em Camada Fina , Cristalografia por Raios X , Análise de Fourier , Glicolipídeos/metabolismo , Humanos , Mutagênese , Espectrometria de Massas por Ionização por Electrospray
16.
Sci Immunol ; 9(95): eadn0126, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38728413

RESUMO

MR1T cells are a recently found class of T cells that recognize antigens presented by the major histocompatibility complex-I-related molecule MR1 in the absence of microbial infection. The nature of the self-antigens that stimulate MR1T cells remains unclear, hampering our understanding of their physiological role and therapeutic potential. By combining genetic, pharmacological, and biochemical approaches, we found that carbonyl stress and changes in nucleobase metabolism in target cells promote MR1T cell activation. Stimulatory compounds formed by carbonyl adducts of nucleobases were detected within MR1 molecules produced by tumor cells, and their abundance and antigenicity were enhanced by drugs that induce carbonyl accumulation. Our data reveal carbonyl-nucleobase adducts as MR1T cell antigens. Recognizing cells under carbonyl stress allows MR1T cells to monitor cellular metabolic changes with physiological and therapeutic implications.


Assuntos
Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Menor , Animais , Humanos , Camundongos , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Ativação Linfocitária/imunologia , Antígenos de Histocompatibilidade Menor/metabolismo , Antígenos de Histocompatibilidade Menor/imunologia , Linfócitos T/imunologia
17.
J Biol Chem ; 287(37): 31494-502, 2012 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-22782895

RESUMO

Lipids are important antigens that induce T cell-mediated specific immune responses. They are presented to T lymphocytes by a specific class of MHC-I like proteins, termed CD1. The majority of the described CD1-presented mycobacterial antigens are presented by the CD1b isoform. We previously demonstrated that the stimulation of CD1b-restricted T cells by the hexamannosylated phosphatidyl-myo-inositol (PIM(6)), a family of mycobacterial antigens, requires a prior partial digestion of the antigen oligomannoside moiety by α-mannosidase and that CD1e is an accessory protein absolutely required for the generation of the lipid immunogenic form. Here, we show that CD1e behaves as a lipid transfer protein influencing lipid immunoediting and membrane transfer of PIM lipids. CD1e selectively assists the α-mannosidase-dependent digestion of PIM(6) species according to their degree of acylation. Moreover, CD1e transfers only diacylated PIM from donor to acceptor liposomes and also from membranes to CD1b. This study provides new insight into the molecular mechanisms by which CD1e contributes to lipid immunoediting and CD1-restricted presentation to T cells.


Assuntos
Apresentação de Antígeno/fisiologia , Antígenos de Bactérias/imunologia , Antígenos CD1/imunologia , Glicolipídeos/imunologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Antígenos de Bactérias/genética , Antígenos de Bactérias/metabolismo , Antígenos CD1/genética , Antígenos CD1/metabolismo , Linhagem Celular , Glicolipídeos/genética , Glicolipídeos/metabolismo , Humanos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Linfócitos T/metabolismo , alfa-Manosidase/química
18.
Indian J Med Res ; 138(5): 620-31, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24434317

RESUMO

The immune system has evolved to recognize a wide range of antigenic molecules of self and non-self origin. The stimulatory antigens form complexes with antigen-presenting molecules and directly interact with the T cell receptor (TCR). Peptidic antigens associate with major histocompatibility complex (MHC) molecules and therefore, are indicated as MHC-restricted. Non-peptidic antigens do not bind to MHC molecules and are presented by other classes of antigen-presenting molecules. These non-MHC restricted antigens include glycolipid molecules, phosphorylated metabolites of the mevalonate pathway and vitamin B2 precursors. T cells specific for non-peptidic antigens have important roles in host defense against infections, autoimmunity, allergies and tumour immunosurveillance. Hence, understanding the molecular interactions between the antigen presenting cell (APC) and the T cells with non-peptidic specificity is of great relevance. Here, we review current knowledge of this type of T cells, their TCR repertoire, the structural aspects of recognized antigens, the mode of antigen recognition, and their function with special emphasis on their role in infectious diseases.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Doenças Transmissíveis/imunologia , Complexo Principal de Histocompatibilidade/imunologia , Linfócitos T/imunologia , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/metabolismo , Antígenos/imunologia , Antígenos/metabolismo , Doenças Transmissíveis/patologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Riboflavina/imunologia , Riboflavina/metabolismo , Linfócitos T/metabolismo
19.
J Exp Med ; 220(9)2023 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-37382893

RESUMO

Mucosal-associated invariant T (MAIT) cells use canonical semi-invariant T cell receptors (TCR) to recognize microbial riboflavin precursors displayed by the antigen-presenting molecule MR1. The extent of MAIT TCR crossreactivity toward physiological, microbially unrelated antigens remains underexplored. We describe MAIT TCRs endowed with MR1-dependent reactivity to tumor and healthy cells in the absence of microbial metabolites. MAIT cells bearing TCRs crossreactive toward self are rare but commonly found within healthy donors and display T-helper-like functions in vitro. Experiments with MR1-tetramers loaded with distinct ligands revealed significant crossreactivity among MAIT TCRs both ex vivo and upon in vitro expansion. A canonical MAIT TCR was selected on the basis of extremely promiscuous MR1 recognition. Structural and molecular dynamic analyses associated promiscuity to unique TCRß-chain features that were enriched within self-reactive MAIT cells of healthy individuals. Thus, self-reactive recognition of MR1 represents a functionally relevant indication of MAIT TCR crossreactivity, suggesting a potentially broader role of MAIT cells in immune homeostasis and diseases, beyond microbial immunosurveillance.


Assuntos
Células T Invariantes Associadas à Mucosa , Humanos , Membrana Celular , Comunicação Celular , Reações Cruzadas , Reparo do DNA , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Menor
20.
Eur J Immunol ; 41(3): 602-10, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21246542

RESUMO

CD1 molecules present lipid antigens to T cells. An intriguing subset of human T cells recognize CD1-expressing cells without deliberately added lipids. Frequency, subset distribution, clonal composition, naïve-to-memory dynamic transition of these CD1 self-reactive T cells remain largely unknown. By screening libraries of T-cell clones, generated from CD4(+) or CD4(-) CD8(-) double negative (DN) T cells sorted from the same donors, and by limiting dilution analysis, we find that the frequency of CD1 self-reactive T cells is unexpectedly high in both T-cell subsets, in the range of 1/10-1/300 circulating T cells. These T cells predominantly recognize CD1a and CD1c and express diverse TCRs. Frequency comparisons of T-cell clones from sorted naïve and memory compartments of umbilical cord and adult blood show that CD1 self-reactive T cells are naïve at birth and undergo an age-dependent increase in the memory compartment, suggesting a naïve/memory adaptive-like population dynamics. CD1 self-reactive clones exhibit mostly Th1 and Th0 functional activities, depending on the subset and on the CD1 isotype restriction. These findings unveil the unanticipated relevance of self-lipid T-cell response in humans and clarify the basic parameters of the lipid-specific T-cell physiology.


Assuntos
Antígenos CD1/metabolismo , Subpopulações de Linfócitos T/imunologia , Imunidade Adaptativa , Adulto , Apresentação de Antígeno , Autoantígenos , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Citotoxicidade Imunológica , Sangue Fetal/citologia , Sangue Fetal/imunologia , Humanos , Imunidade Celular , Memória Imunológica , Técnicas In Vitro , Recém-Nascido , Lipídeos/imunologia , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/citologia
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