RESUMO
Mucosal-associated Invariant T (MAIT) cells recognize vitamin B-based antigens presented by the non-polymorphic MHC class I related-1 molecule (MR1). Both MAIT T cell receptors (TCR) and MR1 are highly conserved among mammals, suggesting an important, and conserved, immune function. For many years, the antigens they recognize were unknown. The discovery that MR1 presents vitamin B-based small molecule ligands resulted in a rapid expansion of research in this area, which has yielded information on the role of MAIT cells in immune protection, autoimmune disease and recently in homeostasis and cancer. More recently, we have begun to appreciate the diverse nature of the small molecule ligands that can bind MR1, with several less potent antigens and small molecule drugs that can bind MR1 being identified. Complementary structural information has revealed the complex nature of interactions defining antigen recognition. Additionally, we now view MAIT cells (defined here as MR1-riboflavin-Ag reactive, TRAV1-2+ cells) as one subset of a broader family of MR1-reactive T cells (MR1T cells). Despite these advances, we still lack a complete understanding of how MR1 ligands are generated, presented and recognized in vivo. The biological relevance of these MR1 ligands and the function of MR1T cells in infection and disease warrants further investigation with new tools and approaches.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Riboflavina/imunologia , Complexo Vitamínico B/imunologia , Animais , Apresentação de Antígeno , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligantes , Antígenos de Histocompatibilidade Menor/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismo , Riboflavina/metabolismo , Complexo Vitamínico B/metabolismoAssuntos
Biotina/uso terapêutico , Erros de Diagnóstico , Hipotireoidismo/diagnóstico , Imunoensaio , Doenças Mitocondriais/tratamento farmacológico , Testes de Função Tireóidea , Complexo Vitamínico B/uso terapêutico , Biomarcadores/sangue , Biotina/imunologia , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/complicações , Lactente , Masculino , Doenças Mitocondriais/sangue , Doenças Mitocondriais/complicações , Complexo Vitamínico B/imunologiaAssuntos
Dessensibilização Imunológica/métodos , Hipersensibilidade a Drogas/tratamento farmacológico , Deficiência de Vitamina B 12/tratamento farmacológico , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Testes Cutâneos , Vitamina B 12/efeitos adversos , Vitamina B 12/imunologia , Complexo Vitamínico B/efeitos adversos , Complexo Vitamínico B/imunologiaRESUMO
Mucosal-associated invariant T cells (MAIT cells) are innate-like T cells that recognise antigens presented by the monomorphic MHC-I related molecule, MR1. Distinct from the conventional MHC-restricted T cell system, MR1 presents small-molecule precursors, derived from microbial biosynthesis of riboflavin, to activate the innate MAIT cell effector potential. Recent data demonstrates how: vitamin B precursors modulate intracellular trafficking of MR1 and impact on MAIT cell development; variation in the MAIT cell antigen receptor sequence impacts MR1-antigen recognition; and most notably, how MR1 can capture chemical identities distinct from riboflavin precursors, including drugs and drug-like molecules. With mounting evidence demonstrating their roles in immunity and pathology, understanding the MAIT-MR1-antigen axis may have profound implications for human diseases.
Assuntos
Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Menor/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Complexo Vitamínico B/imunologia , Animais , Apresentação de Antígeno/imunologia , Infecções Bacterianas , Suscetibilidade a Doenças/imunologia , Suscetibilidade a Doenças/metabolismo , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Inata , Antígenos de Histocompatibilidade Menor/química , Antígenos de Histocompatibilidade Menor/metabolismo , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/metabolismo , Complexo Vitamínico B/metabolismoRESUMO
Increasing evidence indicates that there are various interactions between the nervous system and the immune system, and that the immune system plays an important role in the pathogenesis of depression. Pro-inflammatory cytokines (such as IL-1, IL-6, TNF-α) have been implicated in the neurobiological manifestations of depression. The immune/cytokine network has a powerful influence on the brain. In addition, deficiency in B vitamins has been linked to depression. Hence, greater knowledge of how immune cells change in the presence of vitamin B derivatives could improve understanding of how immune changes may correlate with depression, all of which are discussed herein.
Assuntos
Citocinas/imunologia , Depressão/imunologia , Sistema Imunitário , Complexo Vitamínico B/imunologia , Deficiência de Vitaminas do Complexo B/complicações , Humanos , Interleucina-1/imunologia , Interleucina-6/imunologia , Fator de Necrose Tumoral alfa/imunologiaRESUMO
The antigen-presenting molecule MR1 presents vitamin B-related antigens (VitB antigens) to mucosal-associated invariant T (MAIT) cells through an uncharacterized pathway. We show that MR1, unlike other antigen-presenting molecules, does not constitutively present self-ligands. In the steady state it accumulates in a ligand-receptive conformation within the endoplasmic reticulum. VitB antigens reach this location and form a Schiff base with MR1, triggering a 'molecular switch' that allows MR1-VitB antigen complexes to traffic to the plasma membrane. These complexes are endocytosed with kinetics independent of the affinity of the MR1-ligand interaction and are degraded intracellularly, although some MR1 molecules acquire new ligands during passage through endosomes and recycle back to the surface. MR1 antigen presentation is characterized by a rapid 'off-on-off' mechanism that is strictly dependent on antigen availability.
Assuntos
Apresentação de Antígeno/imunologia , Antígenos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Transdução de Sinais/imunologia , Antígenos/metabolismo , Linhagem Celular , Membrana Celular/imunologia , Membrana Celular/metabolismo , Células Cultivadas , Endocitose/imunologia , Retículo Endoplasmático/imunologia , Retículo Endoplasmático/metabolismo , Endossomos/imunologia , Endossomos/metabolismo , Células HeLa , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Immunoblotting , Espaço Intracelular/imunologia , Espaço Intracelular/metabolismo , Microscopia Confocal , Antígenos de Histocompatibilidade Menor , Ligação Proteica/imunologia , Transporte Proteico/imunologia , Complexo Vitamínico B/imunologiaRESUMO
This study was conducted to investigate the effects of the dietary vitamin myo-inositol (MI), on the immunity and structural integrity of the head kidney and spleen following infection of fish with the major freshwater pathogen bacterial Aeromonas hydrophila. The results demonstrated for the first time that MI deficiency depressed the lysozyme and acid phosphatase (ACP) activities and the complement 3 (C3) and C4 contents in the head kidney and spleen compared with the optimal MI levels, indicating that MI deficiency decreased the immunity of these important fish immune organs. The depression in immunity due to MI deficiency was partially related to oxidative damage [indicated by increases in the malondialdehyde (MDA) and protein carbonyl (PC) contents] that was in turn partially due to the decreased glutathione (GSH) content and the disturbances in antioxidant enzyme activities [total superoxide dismutase (T-SOD), CuZnSOD, MnSOD, catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)]. MI deficiency inhibited the antioxidant-related gene transcription [CuZnSOD, MnSOD, CAT, GPx1a, GR and NF-E2-related factor 2 (Nrf2)] in the head kidney and spleen following infection of the fish with A. hydrophila. The oxidative damage due to MI deficiency also resulted in the inhibition of proliferation-associated signalling (cyclin D1, cyclin A, cyclin E and E2F4). Thus, MI deficiency partially inhibited damage repair. Excessive MI exhibited negative effects that were similar to MI deficiency, whereas the optimal MI content reversed those indicators. These observations indicated that an MI deficiency or excess could cause depression of the immune system that might be partially related to oxidative damage, antioxidant disturbances, and the inhibition of the proliferation-associated signalling in the head kidney and spleen following infection of fish with A. hydrophila. Finally, the optimal MI levels were 660.7 (based on ACP) and 736.8 mg kg(-1) diet (based on MDA) in the head kidney and 770.5 (based on ACP) and 766.9 mg kg(-1) diet (based on MDA) in the spleen of juvenile Jian carp.
Assuntos
Carpas , Fator de Transcrição E2F4/metabolismo , Doenças dos Peixes/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Imunidade Inata/efeitos dos fármacos , Inositol/farmacologia , Fator 2 Relacionado a NF-E2/metabolismo , Aeromonas hydrophila/fisiologia , Animais , Antioxidantes/metabolismo , Fator de Transcrição E2F4/genética , Ativação Enzimática/efeitos dos fármacos , Proteínas de Peixes/genética , Proteínas de Peixes/imunologia , Regulação da Expressão Gênica/efeitos dos fármacos , Infecções por Bactérias Gram-Negativas/imunologia , Rim Cefálico/efeitos dos fármacos , Rim Cefálico/imunologia , Inositol/imunologia , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/efeitos dos fármacos , Oxirredutases/genética , Oxirredutases/metabolismo , Baço/efeitos dos fármacos , Baço/imunologia , Complexo Vitamínico B/imunologia , Complexo Vitamínico B/farmacologiaRESUMO
T cells discriminate between foreign and host molecules by recognizing distinct microbial molecules, predominantly peptides and lipids. Riboflavin precursors found in many bacteria and yeast also selectively activate mucosal-associated invariant T (MAIT) cells, an abundant population of innate-like T cells in humans. However, the genesis of these small organic molecules and their mode of presentation to MAIT cells by the major histocompatibility complex (MHC)-related protein MR1 (ref. 8) are not well understood. Here we show that MAIT-cell activation requires key genes encoding enzymes that form 5-amino-6-d-ribitylaminouracil (5-A-RU), an early intermediate in bacterial riboflavin synthesis. Although 5-A-RU does not bind MR1 or activate MAIT cells directly, it does form potent MAIT-activating antigens via non-enzymatic reactions with small molecules, such as glyoxal and methylglyoxal, which are derived from other metabolic pathways. The MAIT antigens formed by the reactions between 5-A-RU and glyoxal/methylglyoxal were simple adducts, 5-(2-oxoethylideneamino)-6-D-ribitylaminouracil (5-OE-RU) and 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), respectively, which bound to MR1 as shown by crystal structures of MAIT TCR ternary complexes. Although 5-OP-RU and 5-OE-RU are unstable intermediates, they became trapped by MR1 as reversible covalent Schiff base complexes. Mass spectra supported the capture by MR1 of 5-OP-RU and 5-OE-RU from bacterial cultures that activate MAIT cells, but not from non-activating bacteria, indicating that these MAIT antigens are present in a range of microbes. Thus, MR1 is able to capture, stabilize and present chemically unstable pyrimidine intermediates, which otherwise convert to lumazines, as potent antigens to MAIT cells. These pyrimidine adducts are microbial signatures for MAIT-cell immunosurveillance.
Assuntos
Antígenos de Bactérias/imunologia , Antígenos de Bactérias/metabolismo , Ativação Linfocitária/imunologia , Redes e Vias Metabólicas , Pirimidinas/metabolismo , Riboflavina/metabolismo , Subpopulações de Linfócitos T/imunologia , Amino Açúcares/química , Amino Açúcares/imunologia , Amino Açúcares/metabolismo , Apresentação de Antígeno/imunologia , Antígenos de Bactérias/química , Glioxal/química , Glioxal/metabolismo , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade Inata/imunologia , Imunidade nas Mucosas/imunologia , Ligantes , Antígenos de Histocompatibilidade Menor , Modelos Moleculares , Conformação Molecular , Mucosa/imunologia , Pirimidinas/química , Pirimidinas/imunologia , Aldeído Pirúvico/química , Aldeído Pirúvico/metabolismo , Riboflavina/biossíntese , Riboflavina/imunologia , Bases de Schiff/química , Subpopulações de Linfócitos T/citologia , Uracila/análogos & derivados , Uracila/química , Uracila/imunologia , Uracila/metabolismo , Complexo Vitamínico B/imunologia , Complexo Vitamínico B/metabolismoRESUMO
αßT-cell mediated immunity is traditionally characterised by recognition of peptides or lipids presented by the major histocompatibility complex (MHC) or the CD1 family respectively. Recently the antigenic repertoire of αßT-cells has been expanded with the observation that mucosal-associated invariant T-cells (MAIT cells), an abundant population of innate-like T-cells, can recognise metabolites of vitamin B, when presented by the MHC-related protein, MR1. The semi-invariant MAIT T-cell antigen receptor (TCR) recognises riboflavin and folic acid metabolites bound by MR1 in a conserved docking mode, and thus acts like a pattern recognition receptor. Here we review and discuss the recent observations concerning antigen presentation by MR1, the advent of MR1-Ag tetramers that specifically stain MAIT cells, recognition by the MAIT TCR, and our emerging understanding of MAIT cells in disease.
Assuntos
Apresentação de Antígeno/imunologia , Genes MHC Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Complexo Vitamínico B/metabolismo , Animais , Apresentação de Antígeno/genética , Sequência Conservada/genética , Sequência Conservada/imunologia , Rearranjo Gênico da Cadeia alfa dos Receptores de Antígenos dos Linfócitos T/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Imunidade nas Mucosas/genética , Antígenos de Histocompatibilidade Menor , Receptores de Reconhecimento de Padrão/genética , Receptores de Reconhecimento de Padrão/imunologia , Receptores de Reconhecimento de Padrão/metabolismo , Subpopulações de Linfócitos T/patologia , Complexo Vitamínico B/genética , Complexo Vitamínico B/imunologiaRESUMO
Mucosal associated invariant T (MAIT) cells are evolutionarily conserved T cells that are restricted by the non-classical MHC-1b molecule, MR1. MAIT cells are selected on hematopoietic cells, and exit the thymus with a naïve phenotype before expanding in the periphery and attaining a memory phenotype. MAIT cells represent an abundant oligoclonal population in human blood and liver. MAIT cells react against a newly identified class of antigens: vitamin B metabolites, which are found in most bacteria and yeasts. MAIT cells secrete IFN-γ and IL-17 and their frequencies are modified in several diseases. The specificity, evolutionary conservation and unique features of MAIT cells indicate important functions, either against a ubiquitous pathogen or in gut immune/epithelial homeostasis.
Assuntos
Antígenos/imunologia , Linfócitos T/imunologia , Complexo Vitamínico B/imunologia , Complexo Vitamínico B/metabolismo , Animais , Antígenos/metabolismo , Humanos , Linfócitos T/citologiaRESUMO
OBJECTIVES: Folate supplementation may be associated with an increased risk of developing several types of cancer and a derangement of immune function. Among the latter, Natural killer (NK) cells are involved in non-MHC-restricted natural immunity against malignant target cells. Abnormalities in NK cell number or function have been associated with a higher cancer risk. The aim of this study was to study in vitro the possible effect of different concentrations of 5-methyltetrahydrofolic acid (5-MTHF) or folic acid on NK cell cytotoxic function, and expression of the stimulatory and inhibitory receptors KIRDL4, KIRDL3, and NKG2D. METHODS: Volunteer-derived peripheral mononuclear cells (PBMC) and highly enriched NK cells (95% CD56+ CD16+) were grown in folic acid free-RPMI 1640, supplemented either with folic acid or 5-MTHF (15-100 nM) during 72 h to 96 h. RESULTS: No differences in the cytolytic activity of PBMC and enriched NK cells were observed. After 96 h of in vitro culture without folate or supplemented with FA or 5-MTHF (30 or 100 nM), there were no changes in the percentage of HPNK receptor-positive cells. CONCLUSIONS: Our data indicate that a high dose of 5-MTHF or folic acid does not influence NK cell function in vitro.
Assuntos
Citotoxicidade Imunológica/efeitos dos fármacos , Ácido Fólico/farmacologia , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Neoplasias/imunologia , Receptores de Células Matadoras Naturais/metabolismo , Complexo Vitamínico B/farmacologia , Antígeno CD56/metabolismo , Suplementos Nutricionais , Feminino , Ácido Fólico/imunologia , Ácido Fólico/metabolismo , Humanos , Células Matadoras Naturais/metabolismo , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Neoplasias/metabolismo , Receptores de IgG/metabolismo , Tetra-Hidrofolatos/imunologia , Tetra-Hidrofolatos/metabolismo , Tetra-Hidrofolatos/farmacologia , Complexo Vitamínico B/imunologia , Complexo Vitamínico B/metabolismoRESUMO
The importance of diet in multiple aspects of the immune response is inescapable. Although only a few trials have attempted to apply knowledge derived from in-vitro and animal data to humans, the ability to modulate or "reset" the immune response by manipulating dietary intake will surely continue to be studied in the future. The role of various nutrients in immunity is reviewed and clinical applications are noted.