RESUMO
The cluster of differentiation 1 (CD1) molecule differs from major histocompatibility complex class I and II because it presents glycolipid/lipid antigens. Moreover, the CD1-restricted T cells that recognize these self and foreign antigens participate in both innate and adaptive immune responses. CD1s are constitutively expressed by professional and nonprofessional antigen-presenting cells in mucosal tissues, namely, the skin, lung, and intestine. This suggests that CD1-reactive T cells are involved in the immune responses of these tissues. Indeed, evidence suggests that these cells play important roles in diverse diseases, such as inflammation, autoimmune disease, and infection. Recent studies elucidating the molecular mechanisms by which CD1 presents lipid antigens suggest that defects in these mechanisms could contribute to the activities of CD1-reactive T cells. Thus, improving our understanding of these mechanisms could lead to new and effective therapeutic approaches to CD1-associated diseases. In this review, we discuss the CD1-mediated antigen presentation system and its roles in mucosal tissue immunity.
Assuntos
Apresentação de Antígeno , Lipídeos , Antígenos CD1/fisiologia , Linfócitos T , Antígenos , MucosaAssuntos
Antígenos CD1/imunologia , Psoríase/terapia , Desenvolvimento de Vacinas , Antígenos CD1/genética , Antígenos CD1/fisiologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Humanos , Imunoterapia Ativa , Células de Langerhans/imunologia , Lipídeos/imunologia , Ativação Linfocitária , Modelos Imunológicos , Mutação Puntual , Ligação Proteica , Psoríase/imunologia , Subpopulações de Linfócitos T/imunologiaRESUMO
The CD1 antigen presenting system is evolutionary conserved and found in mammals, birds and reptiles. Humans express five isoforms, of which CD1a, CD1b and CD1c represent the group 1 CD1-molecules. They are recognized by T cells that express diverse αß-T cell receptors. Investigation of the role of group 1 CD1 function has been hampered by the fact that CD1a, CD1b and CD1c are not expressed by mice. However, other animals, such as guinea pigs or cattle, serve as alternative models and have established basic aspects of CD1-dependent, antimicrobial immune functions. Group 1 CD1 transgenic mouse models became available about ten years ago. In a series of seminal studies these mouse models coined the mechanistical understanding of the role of the corresponding CD1 restricted T cell responses. This review gives a short overview of available animal studies and the lessons that have been and still can be learned.
Assuntos
Apresentação de Antígeno , Antígenos CD1/fisiologia , Modelos Animais , Animais , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Bovinos , Glicoproteínas/fisiologia , Cobaias , Humanos , Camundongos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
The high expression of CD1a on Langerhans cells in normal human skin suggests a central role for this lipid antigen presenting molecule in skin homeostasis and immunity. Although the lipid antigen presenting function of CD1a has been known for years, the physiological and pathological functions of the CD1a system in human skin remain incompletely understood. This review provides an overview of this active area of investigation, and discusses recent insights into the functions of CD1a, CD1a-restricted T cells, and lipid antigens in inflammatory and allergic skin disease. We include recent publications and work presented at the biennial CD1-MR1 EMBO workshop held in 2019 in Oxford, regarding lipids that increase and those that decrease T cell responses to CD1a.
Assuntos
Antígenos CD1/fisiologia , Dermatopatias/genética , Dermatopatias/imunologia , Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Humanos , Células de Langerhans/imunologia , Células de Langerhans/patologia , Ativação Linfocitária/genética , Pele/imunologia , Dermatopatias/patologia , Linfócitos T/imunologiaRESUMO
OBJECTIVE: This review focuses on the current knowledge on the implication and significance of beta 2 microglobulin (ß2M), a conservative immune molecule in vertebrate. DATA SOURCES: The data used in this review were obtained from PubMed up to October 2015. Terms of ß2M, immune response, and infection were used in the search. STUDY SELECTIONS: Articles related to ß2M were retrieved and reviewed. Articles focusing on the characteristic and function of ß2M were selected. The exclusion criteria of articles were that the studies on ß2M-related molecules. RESULTS: ß2M is critical for the immune surveillance and modulation in vertebrate animals. The dysregulation of ß2M is associated with multiple diseases, including endogenous and infectious diseases. ß2M could directly participate in the development of cancer cells, and the level of ß2M is deemed as a prognostic marker for several malignancies. It also involves in forming major histocompatibility complex (MHC class I or MHC I) or like heterodimers, covering from antigen presentation to immune homeostasis. CONCLUSIONS: Based on the characteristic of ß2M, it or its signaling pathway has been targeted as biomedical or therapeutic tools. Moreover, ß2M is highly conserved among different species, and overall structures are virtually identical, implying the versatility of ß2M on applications.
Assuntos
Microglobulina beta-2/fisiologia , Antígenos CD1/fisiologia , Proteína da Hemocromatose/análise , Antígenos de Histocompatibilidade Classe I/fisiologia , Humanos , Receptores Fc/fisiologia , Microglobulina beta-2/sangue , Microglobulina beta-2/química , Microglobulina beta-2/deficiênciaRESUMO
Although olfactory discrimination has already been studied in several mouse strains, data on protein levels linked to olfactory memory are limited. Wild mouse strains Mus musculus musculus, Mus musculus domesticus and CD1 laboratory outbred mice were tested in a conditioned odor preference task and trained to discriminate between two odors, Rose and Lemon, by pairing one odor with a sugar reward. Six hours following the final test, mice were sacrificed and olfactory bulbs (OB) were taken for gel-based proteomics analyses and immunoblotting. OB proteins were extracted, separated by 2-DE and quantified using specific software (Proteomweaver). Odor-trained mice showed a preference for the previously rewarded odor suggesting that conditioned odor preference occurred. In CD1 mice levels, one out of 482 protein spots was significantly increased in odor-trained mice as compared with the control group; it was in-gel digested by trypsin and chymotrypsin and analyzed by tandem mass spectrometry (nano-ESI-LC-MS/MS). The spot was unambiguously identified as serine/threonine-protein phosphatase PP1-α catalytic subunit (PP-1A) and differential levels observed in gel-based proteomic studies were verified by immunoblotting. PP-1A is a key signalling element in synaptic plasticity and memory processes and is herein shown to be paralleling olfactory discrimination representing olfactory memory.
Assuntos
Memória/fisiologia , Camundongos Endogâmicos/fisiologia , Bulbo Olfatório/metabolismo , Proteína Fosfatase 1/análise , Olfato/fisiologia , Sequência de Aminoácidos , Análise de Variância , Animais , Animais Selvagens/fisiologia , Antígenos CD1/fisiologia , Comportamento Animal , Eletroforese em Gel Bidimensional , Immunoblotting , Imuno-Histoquímica , Aprendizagem , Masculino , Camundongos , Dados de Sequência Molecular , Odorantes , Bulbo Olfatório/química , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Proteína Fosfatase 1/química , Proteína Fosfatase 1/metabolismoRESUMO
Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.
Assuntos
Abetalipoproteinemia/imunologia , Antígenos CD1/fisiologia , Proteínas de Transporte/fisiologia , Adulto , Apresentação de Antígeno , Antígenos CD1d/fisiologia , Células Cultivadas , Feminino , Humanos , Interleucina-12/fisiologia , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Adulto JovemRESUMO
The discovery of molecules capable of presenting lipid antigens, the CD1 family, and of the T cells that recognize them, has opened a new dimensionin our understanding of cell-mediated immunity against infection. Like MHC Class I molecules, CD1 isoforms (CD1a, b, c and d) are assembled in the ER and sent to the cell surface. However, in contrast to MHC molecules, CD1 complexes are then re-internalized into specific endocytic compartments where they can bind lipid antigens. These include a broad scope of both self and foreign molecules that range from simple fatty acids or phospholipids, to more complex glycolipids, isoprenoids, mycolates and lipopeptides. Lipid-loaded CD1 molecules are then delivered to the cell surface and can be surveyed by CD1-restricted T cells expressing alphabeta or gammadelta T Cell Receptors (TCR). It has become clear that T cell-mediated lipid antigen recognition plays an important role in detection and clearance of pathogens. CD1a, b and c-restricted T cells have been found to recognize a number of lipid antigens from M. tuberculosis. CD1d-restricted T cells are the only CD1-restricted T cell subset present in mice, which lack the genes encoding CD1a, b and c. Evidence from experiments in CD1d-restricted T cell-deficient mice indicates that these cells play an important role in the immune response against awide range of pathogens including several bacteria, viruses and parasites. One subset of CD1d-restricted T cells in particular, invariant Natural Killer T (iNKT) cells, has been extensively studied. iNKT cells are characterized by the expression of a semi-invariant TCR composed of a strictly conserved alpha chain paired with a limited repertoire of beta chains. During infection, iNKT cells are rapidly elicited. Activated iNKT cells can produce a vast array of cytokines that profoundly affect both the innate and the adaptive arms of the immune response. In this review, we describe the pathways and mechanisms of lipid antigen binding and presentation by CD1 in detail, as well as the diverse roles played by CD1-restricted T cells in the context of microbial infection.
Assuntos
Apresentação de Antígeno , Antígenos CD1/fisiologia , Bactérias/imunologia , Fungos/imunologia , Células T Matadoras Naturais/imunologia , Parasitos/imunologia , Linfócitos T/imunologia , Animais , Antígenos CD1/química , Endocitose , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/química , Receptores para Leptina/fisiologiaRESUMO
CD1-restricted lipid-specific T lymphocytes are primed during infection with Mycobacterium tuberculosis, the causative agent of tuberculosis. Here we describe the antigenicity of glycerol monomycolate (GroMM), which stimulates CD1b-restricted CD4(+) T cell clones. Chemical characterization of this antigen showed that it exists as two stereoisomers, one synthetic isomer being more stimulatory than the other. The hydroxyl groups of glycerol and the mycolic acid length are critical for triggering the T cell responses. GroMM was presented by M. tuberculosis-infected dendritic cells, demonstrating that the antigen is available for presentation during natural infection. Ex vivo experiments showed that GroMM stimulated T cells from vaccinated or latently infected healthy donors but not cells from patients with active tuberculosis, suggesting that GroMM-specific T cells are primed during infection and their detection correlates with lack of clinical active disease.
Assuntos
Antígenos de Bactérias/imunologia , Antígenos CD1/fisiologia , Monoglicerídeos/imunologia , Mycobacterium tuberculosis/imunologia , Ácidos Micólicos/imunologia , Linfócitos T/imunologia , Antígenos de Bactérias/química , Antígenos CD4/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Humanos , Ativação Linfocitária , Modelos Estruturais , Monoglicerídeos/química , Tuberculose/imunologiaRESUMO
Invariant CD1d restricted natural killer T (iNKT) cells are regulatory cells that express a canonical TCR-Valpha-chain (Valpha24.Jalpha18 in humans and Valpha14.Jalpha18 in mice) which recognizes glycolipid antigens presented by the monomorphic CD1d molecule. They can secrete a wide variety of both pro-inflammatory and anti-inflammatory cytokines very swiftly upon their activation. Evidence for the significance of iNKT cells in human cancer has been ambiguous. Still, the (pre-)clinical findings reviewed here, provide evidence for a distinct contribution of iNKT cells to natural anti-tumor immune responses in humans. Furthermore, clinical phase I studies that are discussed here have revealed that the infusion of cancer patients with ligand-loaded dendritic cells or cultured iNKT cells is well tolerated. We thus underscore the potential of iNKT cell based immunotherapy in conjunction with established modalities such as surgery and radiotherapy, as adjuvant therapy against carcinomas.
Assuntos
Imunoterapia Adotiva , Células Matadoras Naturais/imunologia , Neoplasias/imunologia , Animais , Antígenos CD1/fisiologia , Antígenos CD1d , Linhagem Celular , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/imunologia , Neoplasias/terapiaRESUMO
Invariant NKT cells are CD1d-restricted T cells specific for glycolipid Ags. Their activation or transgenic enrichment abrogates the development of experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate that in NKT-enriched mice the protection from EAE is associated with the infiltration of NKT cells in the CNS and the local expression of CD1d. This indicates that the CNS acquires the potential for local glycolipid presentation when exposed to inflammatory stress, permitting the triggering of NKT cells. To address the importance of CD1d-mediated Ag presentation, we used transgenic mice that express CD1d solely in the thymus. Interestingly, enrichment of NKT cells in these mice also conferred resistance to EAE, with an efficacy indistinguishable from that of NKT-enriched CD1d-sufficient mice. This protection was due to an abrogation of the encephalitogenic Th1 and Th17 response in the spleen, revealing that endogenous glycolipid presentation is dispensable for the regulatory function of NKT cells in EAE. Moreover, abrogating extrathymic CD1d expression failed to affect both the recruitment of NKT cells and their effector phenotype. CNS-infiltrating NKT cells were characterized by a cytotoxic IFN-gamma(high)IL-4(low)IL-10(low)granzyme B(high) profile, irrespective of the local expression of CD1d. Glycolipid Ag presentation is therefore dispensable for the control of autoimmune demyelination by NKT cells, underlining the importance of alternative cognate and/or soluble factors in the control of NKT cell function.
Assuntos
Antígenos CD1/fisiologia , Movimento Celular/imunologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/prevenção & controle , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/patologia , Sequência de Aminoácidos , Animais , Antígenos CD1/biossíntese , Antígenos CD1/genética , Antígenos CD1d , Técnicas de Cocultura , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/patologia , Humanos , Células Matadoras Naturais/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Subpopulações de Linfócitos T/metabolismoRESUMO
Invariant natural killer T (iNKT) cells are a special subset of alphabeta T cells with invariant TCR, which recognize alpha-galactosylceramide (alpha-GalCer) presented by CD1d. In addition to signals through the invariant TCR upon stimulation with alpha-GalCer, costimulatory signals, such as signals through CD28 and OX40, are indispensable for full activation of iNKT cells. In this study, we investigated the functions of a well-known costimulatory molecule, glucocorticoid-induced TNF receptor (GITR), on Ag-induced iNKT cell activation. Unexpectedly, engagement of GITR by agonistic mAb DTA-1 suppressed proliferation and cytokine production of iNKT cells upon alpha-GalCer stimulation. In addition, GITR signals in iNKT cells during only the Ag-priming phase was sufficient to inhibit the iNKT cell activation. Consistent with these results, the GITR-deficient iNKT cells showed enhanced proliferation and increased cytokine production upon alpha-GalCer stimulation both in vitro and in vivo. Furthermore, the in vivo administration of alpha-GalCer suppressed tumor metastasis more efficiently in GITR-deficient mice than in wild-type mice. Collectively, GITR plays a co-inhibitory role in Ag-induced iNKT cell activation.
Assuntos
Antígenos CD1/fisiologia , Glucocorticoides/farmacologia , Células Matadoras Naturais/imunologia , Receptores do Fator de Necrose Tumoral/fisiologia , Animais , Antígenos CD1d , Citotoxicidade Imunológica , Galactosilceramidas/farmacologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Lipid antigens are presented to T cells by the non-polymorphic MHC class I-related CD1 molecules. Microsomal triglyceride transfer protein (MTP) is an endoplasmic reticulum (ER)-resident chaperone that has been shown to lipidate the group 2 CD1 molecule CD1d and thus to regulate its function. We now report that MTP also regulates the function of group 1 CD1 molecules CD1a, CD1b, and CD1c. Pharmacological inhibition of MTP in monocyte-derived dendritic cells and lymphoblastoid B cell lines transfected with group 1 CD1 resulted in a substantial decrease in endogenous self lipid antigen presentation to several CD1-restricted T cell lines. Silencing MTP expression in CD1c-transfected HeLa cells similarly resulted in decreased self reactivity. Unexpectedly, inhibition of ER-resident MTP, which was confirmed by confocal microscopy, also markedly decreased presentation of exogenous, endosomally loaded, mycobacterial lipid antigens by CD1a and CD1c to T cells. Thus, these studies indicate that MTP, despite its ER localization, regulates endogenous as well as exogenous lipid antigen presentation, and suggest a broad role for MTP in the regulation of CD1 antigen presentation.
Assuntos
Apresentação de Antígeno , Antígenos CD1/fisiologia , Proteínas de Transporte/fisiologia , Glicoproteínas/fisiologia , Células HeLa , HumanosRESUMO
Invariant natural killer T (iNKT) cells are innate lymphocytes whose functions are regulated by self and foreign glycolipid antigens presented by the antigen-presenting molecule CD1d. Activation of iNKT cells in vivo results in rapid release of copious amounts of effector cytokines and chemokines with which they regulate innate and adaptive immune responses to pathogens, certain types of cancers and self-antigens. The nature of CD1d-restricted antigens, the manner in which they are recognised and the unique effector functions of iNKT cells suggest an innate immunoregulatory role for this subset of T cells. Their ability to respond fast and our ability to steer iNKT cell cytokine response to altered lipid antigens make them an important target for vaccine design and immunotherapies against autoimmune diseases. This review summarises our current understanding of CD1d-restricted antigen presentation, the recognition of such antigens by an invariant T-cell receptor on iNKT cells, and the functional consequences of these interactions.
Assuntos
Antígenos CD1/fisiologia , Antígenos/química , Glicolipídeos/química , Animais , Apresentação de Antígeno , Antígenos CD1/imunologia , Antígenos CD1d , Autoantígenos/química , Doenças Autoimunes/metabolismo , Membrana Celular/metabolismo , Humanos , Sistema Imunitário , Células Matadoras Naturais/metabolismo , Modelos Biológicos , Neoplasias/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
Choroidal neovascularization (CNV) is directly related to visual loss in age-related macular degeneration and other macular disorders. We have investigated the role of CD1d-restricted invariant natural killer T (NKT) cells in laser-induced experimental CNV. Quantitative real-time PCR detected increased expression of NKT cell-related genes (Valpha14 and CXCL16) in whole eyes undergoing CNV, indicating local accumulation of NKT cells. We found a significant reduction of CNV and lower concentrations of vascular endothelial growth factor (VEGF) in ocular fluid in two different NKT cell-deficient mice, CD1d knockout (KO) and Jalpha18 KO mice. We also established in vitro co-cultures of retinal pigment epithelial cells and splenic NKT cells, and confirmed NKT cells could produce VEGF in the dish. Moreover, inoculating alpha-galactosylceramide, the ligand for NKT cells, into the vitreous cavity of C57BL/6 mice promoted CNV. We concluded that NKT cells play an important role in CNV as an inducer of VEGF.
Assuntos
Antígenos CD1/fisiologia , Neovascularização de Coroide/imunologia , Células Matadoras Naturais/imunologia , Linfócitos T/imunologia , Animais , Anticorpos/imunologia , Antígenos CD1/genética , Antígenos CD1d , Quimiocina CXCL16 , Quimiocina CXCL6/genética , Neovascularização de Coroide/induzido quimicamente , Neovascularização de Coroide/genética , Técnicas de Cocultura , Modelos Animais de Doenças , Células Epiteliais/citologia , Feminino , Galactosilceramidas/toxicidade , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Interleucina-6/genética , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Epitélio Pigmentado Ocular/citologia , Baço/citologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
There are many mechanisms that regulate and dampen the immune response to cancers, including several types of regulatory T cells. Besides the T reg cell, we have identified another immunoregulatory circuit initiated by NKT cells that produce IL-13 in response to tumor growth and this IL-13 then induces myeloid cells to make TGF-beta that inhibits cytotoxic T cell-mediated tumor immunosurveillance in several mouse tumor models. This finding created a paradox in the role of NKT cells in tumor immunity, in that they can also contribute to protection. We resolve this paradox by the finding that the suppressive NKT cell is a type II NKT cell that lacks the canonical invariant T cell receptor, whereas the protective cell is a type I NKT cell that expresses the invariant receptor. Further, we see that these two subsets of NKT cells counter-regulate each other, defining a new immunoregulatory axis. The balance along this axis may determine the outcome of tumor immunosurveillance as well as influence the efficacy of anti-cancer vaccines and immunotherapy.
Assuntos
Fibrossarcoma/imunologia , Células Matadoras Naturais/imunologia , Sarcoma Experimental/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Antígenos CD1/fisiologia , Fibrossarcoma/patologia , Tolerância Imunológica , Vigilância Imunológica , Interleucina-13/imunologia , Interleucina-13/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Sarcoma Experimental/patologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
The human CD1a-d proteins are plasma membrane molecules involved in the presentation of lipid Ags to T cells. In contrast, CD1e is an intracellular protein present in a soluble form in late endosomes or lysosomes and is essential for the processing of complex glycolipid Ags such as hexamannosylated phosphatidyl-myo-inositol, PIM(6). CD1e is formed by the association of beta(2)-microglobulin with an alpha-chain encoded by a polymorphic gene. We report here that one variant of CD1e with a proline at position 194, encoded by allele 4, does not assist PIM(6) presentation to CD1b-restricted specific T cells. The immunological incompetence of this CD1e variant is mainly due to inefficient assembly and poor transport of this molecule to late endosomal compartments. Although the allele 4 of CD1E is not frequent in the population, our findings suggest that homozygous individuals might display an altered immune response to complex glycolipid Ags.
Assuntos
Apresentação de Antígeno/genética , Apresentação de Antígeno/imunologia , Antígenos CD1/genética , Antígenos CD1/metabolismo , Glicoproteínas/metabolismo , Mutação , Alelos , Substituição de Aminoácidos/genética , Substituição de Aminoácidos/imunologia , Animais , Antígenos CD1/fisiologia , Linhagem Celular Tumoral , Células Clonais , Endossomos/genética , Endossomos/imunologia , Endossomos/metabolismo , Gangliosídeos/genética , Gangliosídeos/metabolismo , Glicolipídeos/genética , Glicolipídeos/metabolismo , Glicolipídeos/fisiologia , Glicoproteínas/genética , Glicoproteínas/fisiologia , Humanos , Polimorfismo Genético , Processamento de Proteína Pós-Traducional/imunologia , Transporte Proteico/genética , Transporte Proteico/imunologiaRESUMO
Natural Killer T (NKT) cells can effect both T cell development and peripheral immune responses through T(H)1/T(H)2 cytokines. Some humans with Type 1 Diabetes Mellitus (T1DM) have numerical and functional NKT deficiencies that contribute to disease severity. Correcting these deficiencies inhibits diabetes in the non-obese diabetic (NOD) T1DM model, which shares similar deficiencies. Here we show that antibodies to CD1d, when given during early thymic development, induce specific increases in surface TCR of developing NOD and C57BL/6 CD4(+)CD8(+) (DP) invariant NKT (iNKT) cells. However, the addition of anti-CD1d causes distinct strain-specific population changes in response to treatment. These changes include: (1) a dose-dependent increase in NOD iNKT(TCR)(+) cells and, conversely, (2) an inhibition of B6 iNKT(TCR)(+) cell production. The observed NOD iNKT expansions correlated with diabetes inhibition in an in vitro T1DM system, suggesting that intrathymic anti-CD1d treatment may correct NOD numerical iNKT deficiencies through developmental TCR enhancement.
Assuntos
Anticorpos/farmacologia , Antígenos CD1/fisiologia , Diabetes Mellitus Tipo 1/imunologia , Células Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Timo/imunologia , Animais , Anticorpos/uso terapêutico , Antígenos CD1/análise , Antígenos CD1/imunologia , Antígenos CD1d , Diabetes Mellitus Tipo 1/terapia , Galactosilceramidas/farmacologia , Camundongos , Camundongos Endogâmicos NOD , Linfócitos T/fisiologiaRESUMO
CD1 molecules present a variety of microbial glycolipids and self-glycolipids to T cells, but their potential role in humoral responses to glycolipid Ags remains to be established. To address this issue directly, we used GM1/GD1a-deficient mice, which, upon immunization with heat-killed Campylobacter jejuni, develop Guillain-Barré syndrome-associated IgG Abs against the GM1/GD1a sugar chain epitopes of bacterial lipo-oligosaccharides (LOS). Our results showed that anti-ganglioside Abs of the IgG1, IgG2b, and IgG3 isotypes were produced in the absence of group 2 CD1 (CD1d) expression. Unlike mouse and human group 2 CD1 molecules that specifically bound LOS, none of the group 1 CD1 molecules (CD1a, CD1b, and CD1c in humans) were capable of interacting with LOS. Thus, these results indicate CD1-independent pathways for anti-ganglioside Ab production.
Assuntos
Formação de Anticorpos , Antígenos CD1/fisiologia , Gangliosídeos/imunologia , Síndrome de Guillain-Barré/imunologia , Imunoglobulina G/metabolismo , Animais , Anticorpos/imunologia , Campylobacter jejuni/imunologia , Gangliosídeo G(M1)/análogos & derivados , Gangliosídeo G(M1)/genética , Lipopolissacarídeos/imunologia , Camundongos , Camundongos MutantesRESUMO
Valpha14 invariant (Valpha14i) NK T cell development is unique from mainstream T cell selection, and the polygenic factors that influence NK T cell ontogeny are still unclear. In this study, we report the absence of Valpha14i NK T cells in B6.IFN-alphabetaR1-/- male mice, whereas both the conventional T and NK cell populations are relatively unaffected. The lack of Valpha14i NK T cells in the B6.IFN-alphabetaR1-/- males is not due to an insufficient level of CD1d1 or a defect in CD1d1-Ag presentation, but it is intrinsic to the male Valpha14i NK T cells. This surprising defect displays >or=99% penetrance in the male population, whereas female mice remain unaffected, indicating the deficiency is not X linked. Analysis of the Valpha14i NK T cell compartment in B6.Tyk2-/-, B6.STAT1-/-, 129.IFN-alphabetaR1-/-, and B6.IFN-alphabetaR1-/+ mice demonstrate that the deficiency is linked to the Y chromosome, but independent of IFN-alphabeta. This is the first study demonstrating that Y-linked genes can exclusively impact Valpha14i NK T development and further highlight the unique ontogeny of these innate T cells.