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1.
Annu Rev Immunol ; 37: 497-519, 2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31026413

RESUMO

During development innate lymphoid cells and specialized lymphocyte subsets colonize peripheral tissues, where they contribute to organogenesis and later constitute the first line of protection while maintaining tissue homeostasis. A few of these subsets are produced only during embryonic development and remain in the tissues throughout life. They are generated through a unique developmental program initiated in lympho-myeloid-primed progenitors, which lose myeloid and B cell potential. They either differentiate into innate lymphoid cells or migrate to the thymus to give rise to embryonic T cell receptor-invariant T cells. At later developmental stages, adaptive T lymphocytes are derived from lympho-myeloid progenitors that colonize the thymus, while lymphoid progenitors become specialized in the production of B cells. This sequence of events highlights the requirement for stratification in the establishment of immune functions that determine efficient seeding of peripheral tissues by a limited number of cells.


Assuntos
Linfócitos B/imunologia , Linfócitos/fisiologia , Células Progenitoras Linfoides/fisiologia , Células T Matadoras Naturais/imunologia , Timo/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Microambiente Celular , Citocinas/metabolismo , Humanos , Imunidade Inata , Ativação Linfocitária , Comunicação Parácrina , Transcriptoma
2.
Annu Rev Immunol ; 32: 323-66, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24499274

RESUMO

Over the past 15 years, investigators have shown that T lymphocytes can recognize not only peptides in the context of MHC class I and class II molecules but also foreign and self-lipids in association with the nonclassical MHC class I-like molecules, CD1 proteins. In this review, we describe the most recent events in the field, with particular emphasis on (a) structural and functional aspects of lipid presentation by CD1 molecules, (b) the development of CD1d-restricted invariant natural killer T (iNKT) cells and transcription factors required for their differentiation, (c) the ability of iNKT cells to modulate innate and adaptive immune responses through their cross talk with lymphoid and myeloid cells, and (d) MR1-restricted and group I (CD1a, CD1b, and CD1c)-restricted T cells.


Assuntos
Antígenos CD1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1/metabolismo , Diferenciação Celular , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligantes , Ativação Linfocitária/imunologia , Antígenos de Histocompatibilidade Menor , Mucosa/citologia , Mucosa/imunologia , Mucosa/metabolismo , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Ligação Proteica/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T/imunologia
3.
Annu Rev Immunol ; 31: 413-41, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23298206

RESUMO

NKG2D is an activating receptor expressed by all NK cells and subsets of T cells. It serves as a major recognition receptor for detection and elimination of transformed and infected cells and participates in the genesis of several inflammatory diseases. The ligands for NKG2D are self-proteins that are induced by pathways that are active in certain pathophysiological states. NKG2D ligands are regulated transcriptionally, at the level of mRNA and protein stability, and by cleavage from the cell surface. In some cases, ligand induction can be attributed to pathways that are activated specifically in cancer cells or infected cells. We review the numerous pathways that have been implicated in the regulation of NKG2D ligands, discuss the pathologic states in which those pathways are likely to act, and attempt to synthesize the findings into general schemes of NKG2D ligand regulation in NK cell responses to cancer and infection.


Assuntos
Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Animais , Humanos , Células Matadoras Naturais/patologia , Ligantes , Camundongos , Subfamília K de Receptores Semelhantes a Lectina de Células NK/biossíntese , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Células T Matadoras Naturais/patologia
4.
Cell ; 173(5): 1123-1134.e11, 2018 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-29775592

RESUMO

Genome-wide association studies have identified risk loci associated with the development of inflammatory bowel disease, while epidemiological studies have emphasized that pathogenesis likely involves host interactions with environmental elements whose source and structure need to be defined. Here, we identify a class of compounds derived from dietary, microbial, and industrial sources that are characterized by the presence of a five-membered oxazole ring and induce CD1d-dependent intestinal inflammation. We observe that minimal oxazole structures modulate natural killer T cell-dependent inflammation by regulating lipid antigen presentation by CD1d on intestinal epithelial cells (IECs). CD1d-restricted production of interleukin 10 by IECs is limited through activity of the aryl hydrocarbon receptor (AhR) pathway in response to oxazole induction of tryptophan metabolites. As such, the depletion of the AhR in the intestinal epithelium abrogates oxazole-induced inflammation. In summary, we identify environmentally derived oxazoles as triggers of CD1d-dependent intestinal inflammatory responses that occur via activation of the AhR in the intestinal epithelium.


Assuntos
Colite/patologia , Dieta , Intestinos/patologia , Oxazóis/farmacologia , Receptores de Hidrocarboneto Arílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos CD1d/genética , Antígenos CD1d/metabolismo , Colite/induzido quimicamente , Colite/metabolismo , Modelos Animais de Doenças , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Interleucina-10/metabolismo , Intestinos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/imunologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/genética , Triptofano/metabolismo
5.
Nat Immunol ; 21(9): 1058-1069, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719520

RESUMO

Innate T cells, including invariant natural killer T (iNKT) and mucosal-associated innate T (MAIT) cells, are a heterogeneous T lymphocyte population with effector properties preprogrammed during their thymic differentiation. How this program is initiated is currently unclear. Here, we show that the transcription factor BCL-6 was transiently expressed in iNKT cells upon exit from positive selection and was required for their proper development beyond stage 0. Notably, development of MAIT cells was also impaired in the absence of Bcl6. BCL-6-deficient iNKT cells had reduced expression of genes that were associated with the innate T cell lineage, including Zbtb16, which encodes PLZF, and PLZF-targeted genes. BCL-6 contributed to a chromatin accessibility landscape that was permissive for the expression of development-related genes and inhibitory for genes associated with naive T cell programs. Our results revealed new functions for BCL-6 and illuminated how this transcription factor controls early iNKT cell development.


Assuntos
Cromatina/metabolismo , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Animais , Diferenciação Celular , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Regulação da Expressão Gênica no Desenvolvimento , Imunidade Inata , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína com Dedos de Zinco da Leucemia Promielocítica/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética
6.
Nat Immunol ; 20(12): 1644-1655, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31636468

RESUMO

Invariant natural killer T (iNKT) cells recognize activating self and microbial lipids presented by CD1d. CD1d can also bind non-activating lipids, such as sphingomyelin. We hypothesized that these serve as endogenous regulators and investigated humans and mice deficient in acid sphingomyelinase (ASM), an enzyme that degrades sphingomyelin. We show that ASM absence in mice leads to diminished CD1d-restricted antigen presentation and iNKT cell selection in the thymus, resulting in decreased iNKT cell levels and resistance to iNKT cell-mediated inflammatory conditions. Defective antigen presentation and decreased iNKT cells are also observed in ASM-deficient humans with Niemann-Pick disease, and ASM activity in healthy humans correlates with iNKT cell phenotype. Pharmacological ASM administration facilitates antigen presentation and restores the levels of iNKT cells in ASM-deficient mice. Together, these results demonstrate that control of non-agonistic CD1d-associated lipids is critical for iNKT cell development and function in vivo and represents a tight link between cellular sphingolipid metabolism and immunity.


Assuntos
Inflamação/imunologia , Células T Matadoras Naturais/imunologia , Doenças de Niemann-Pick/genética , Esfingomielina Fosfodiesterase/metabolismo , Esfingomielinas/imunologia , Timo/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1d/metabolismo , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Terapia de Reposição de Enzimas , Humanos , Ativação Linfocitária , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Esfingomielina Fosfodiesterase/genética , Esfingomielinas/metabolismo
7.
Nat Immunol ; 20(4): 447-457, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30833791

RESUMO

Invariant natural killer T cells (iNKT cells) develop through an incompletely understood process that requires positive selection by CD4+CD8+ double-positive thymocytes and SLAM family receptors (SFRs). Here we found that SFRs promoted the development of iNKT cells by reducing the strength of the T cell antigen receptor (TCR) signal after positive selection. This effect improved the survival of iNKT cells and their responses to antigen. Loss of SFRs upregulated the expression of inhibitory receptors, including PD-1, on iNKT cells to mitigate the deleterious effect of SFR deficiency. The role of SFRs could be mimicked by expression of SLAMF6 alone in SFR-deficient mice, and this involved the adaptor SAP-kinase Fyn complex and the phosphatase SHP-1. Thus, SFRs foster iNKT cell development by attenuating TCR signal strength after positive selection.


Assuntos
Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/fisiologia , Animais , Proliferação de Células , Sobrevivência Celular , Receptores Coestimuladores e Inibidores de Linfócitos T/metabolismo , Humanos , Camundongos , Camundongos Knockout , Células T Matadoras Naturais/enzimologia , Proteína Tirosina Fosfatase não Receptora Tipo 6/genética , Proteína Tirosina Fosfatase não Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Proto-Oncogênicas c-fyn/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo
8.
Immunity ; 54(11): 2497-2513.e9, 2021 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-34562377

RESUMO

Innate-like T cell populations expressing conserved TCRs play critical roles in immunity through diverse developmentally acquired effector functions. Focusing on the prototypical lineage of invariant natural killer T (iNKT) cells, we sought to dissect the mechanisms and timing of fate decisions and functional effector differentiation. Utilizing induced expression of the semi-invariant NKT cell TCR on double positive thymocytes, an initially highly synchronous wave of iNKT cell development was triggered by brief homogeneous TCR signaling. After reaching a uniform progenitor state characterized by IL-4 production potential and proliferation, effector subsets emerged simultaneously, but then diverged toward different fates. While NKT17 specification was quickly completed, NKT1 cells slowly differentiated and expanded. NKT2 cells resembled maturing progenitors, which gradually diminished in numbers. Thus, iNKT subset diversification occurs in dividing progenitor cells without acute TCR input but utilizes multiple active cytokine signaling pathways. These data imply a two-step model of iNKT effector differentiation.


Assuntos
Citocinas/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Biomarcadores , Diferenciação Celular/imunologia , Ativação Linfocitária/imunologia
9.
Immunity ; 54(7): 1578-1593.e5, 2021 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-34051147

RESUMO

Immune profiling of COVID-19 patients has identified numerous alterations in both innate and adaptive immunity. However, whether those changes are specific to SARS-CoV-2 or driven by a general inflammatory response shared across severely ill pneumonia patients remains unknown. Here, we compared the immune profile of severe COVID-19 with non-SARS-CoV-2 pneumonia ICU patients using longitudinal, high-dimensional single-cell spectral cytometry and algorithm-guided analysis. COVID-19 and non-SARS-CoV-2 pneumonia both showed increased emergency myelopoiesis and displayed features of adaptive immune paralysis. However, pathological immune signatures suggestive of T cell exhaustion were exclusive to COVID-19. The integration of single-cell profiling with a predicted binding capacity of SARS-CoV-2 peptides to the patients' HLA profile further linked the COVID-19 immunopathology to impaired virus recognition. Toward clinical translation, circulating NKT cell frequency was identified as a predictive biomarker for patient outcome. Our comparative immune map serves to delineate treatment strategies to interfere with the immunopathologic cascade exclusive to severe COVID-19.


Assuntos
COVID-19/imunologia , SARS-CoV-2/patogenicidade , Adulto , Enzima de Conversão de Angiotensina 2/metabolismo , Apresentação de Antígeno , Biomarcadores/sangue , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , COVID-19/patologia , Feminino , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunidade Inata , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Células T Matadoras Naturais/imunologia , Pneumonia/imunologia , Pneumonia/patologia , SARS-CoV-2/imunologia , Índice de Gravidade de Doença , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
10.
Cell ; 156(1-2): 123-33, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24439373

RESUMO

Coevolution of beneficial microorganisms with the mammalian intestine fundamentally shapes mammalian physiology. Here, we report that the intestinal microbe Bacteroides fragilis modifies the homeostasis of host invariant natural killer T (iNKT) cells by supplementing the host's endogenous lipid antigen milieu with unique inhibitory sphingolipids. The process occurs early in life and effectively impedes iNKT cell proliferation during neonatal development. Consequently, total colonic iNKT cell numbers are restricted into adulthood, and hosts are protected against experimental iNKT cell-mediated, oxazolone-induced colitis. In studies with neonatal mice lacking access to bacterial sphingolipids, we found that treatment with B. fragilis glycosphingolipids-exemplified by an isolated peak (MW = 717.6) called GSL-Bf717-reduces colonic iNKT cell numbers and confers protection against oxazolone-induced colitis in adulthood. Our results suggest that the distinctive inhibitory capacity of GSL-Bf717 and similar molecules may prove useful in the treatment of autoimmune and allergic disorders in which iNKT cell activation is destructive.


Assuntos
Bacteroides fragilis/metabolismo , Colite/imunologia , Glicoesfingolipídeos/metabolismo , Células T Matadoras Naturais/imunologia , Animais , Animais Recém-Nascidos , Proliferação de Células , Colite/induzido quimicamente , Colite/prevenção & controle , Colo/crescimento & desenvolvimento , Colo/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Células T Matadoras Naturais/citologia , Oxazolona
12.
Nat Immunol ; 17(12): 1407-1414, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27798616

RESUMO

The innate responsiveness of the immune system is important not only for quick responses to pathogens but also for the initiation and shaping of the subsequent adaptive immune response. Activation via the cytokine IL-18, a product of inflammasomes, gives rise to a rapid response that includes the production of self-reactive antibodies. As increased concentrations of this cytokine are found in inflammatory diseases, we investigated the origin of the B cell response and its regulation. We identified an accumulation of B cell-helper neutrophils in the spleen that interacted with innate-type invariant natural killer T cells (iNKT cells) to regulate B cell responses. We found that neutrophil-dependent expression of the death-receptor ligand FasL by iNKT cells was needed to restrict autoantibody production. Neutrophils can thus license iNKT cells to regulate potentially harmful autoreactive B cell responses during inflammasome-driven inflammation.


Assuntos
Linfócitos B/imunologia , Proteína Ligante Fas/metabolismo , Inflamação/imunologia , Células T Matadoras Naturais/imunologia , Neutrófilos/imunologia , Imunidade Adaptativa , Animais , Autoanticorpos/biossíntese , Células Cultivadas , Proteína Ligante Fas/genética , Imunidade Inata , Inflamassomos/metabolismo , Interleucina-18/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
13.
Nat Immunol ; 17(6): 728-39, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27089380

RESUMO

Natural killer T cells (NKT cells) have stimulatory or inhibitory effects on the immune response that can be attributed in part to the existence of functional subsets of NKT cells. These subsets have been characterized only on the basis of the differential expression of a few transcription factors and cell-surface molecules. Here we have analyzed purified populations of thymic NKT cell subsets at both the transcriptomic level and epigenomic level and by single-cell RNA sequencing. Our data indicated that despite their similar antigen specificity, the functional NKT cell subsets were highly divergent populations with many gene-expression and epigenetic differences. Therefore, the thymus 'imprints' distinct gene programs on subsets of innate-like NKT cells that probably impart differences in proliferative capacity, homing, and effector functions.


Assuntos
Regulação da Expressão Gênica , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Células T Matadoras Naturais/imunologia , Timo/imunologia , Animais , Antígenos CD1d/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Células Cultivadas , Epigênese Genética , Regulação da Expressão Gênica/imunologia , Histona Desmetilases com o Domínio Jumonji/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Análise de Célula Única , Transcriptoma
14.
Nat Immunol ; 16(11): 1114-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26482978

RESUMO

While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib-reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.


Assuntos
Subpopulações de Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1/química , Antígenos CD1/metabolismo , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Camundongos , Modelos Imunológicos , Estrutura Molecular , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
15.
Nat Immunol ; 16(1): 85-95, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25436972

RESUMO

Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.


Assuntos
Tecido Adiposo/imunologia , Fatores de Transcrição Kruppel-Like/biossíntese , Macrófagos/imunologia , Células T Matadoras Naturais/metabolismo , Linfócitos T Reguladores/metabolismo , Tecido Adiposo/citologia , Animais , Fatores de Transcrição de Zíper de Leucina Básica/genética , Fatores de Transcrição de Zíper de Leucina Básica/imunologia , Processos de Crescimento Celular/imunologia , Feminino , Citometria de Fluxo , Regulação da Expressão Gênica , Homeostase/imunologia , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-2/genética , Interleucina-2/imunologia , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/imunologia , Macrófagos/citologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/imunologia , Proteína com Dedos de Zinco da Leucemia Promielocítica , Organismos Livres de Patógenos Específicos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia
16.
Nat Immunol ; 16(8): 819-828, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26147686

RESUMO

Fat-associated lymphoid clusters (FALCs) are a type of lymphoid tissue associated with visceral fat. Here we found that the distribution of FALCs was heterogeneous, with the pericardium containing large numbers of these clusters. FALCs contributed to the retention of B-1 cells in the peritoneal cavity through high expression of the chemokine CXCL13, and they supported B cell proliferation and germinal center differentiation during peritoneal immunological challenges. FALC formation was induced by inflammation, which triggered the recruitment of myeloid cells that expressed tumor-necrosis factor (TNF) necessary for signaling via the TNF receptors in stromal cells. Natural killer T cells (NKT cells) restricted by the antigen-presenting molecule CD1d were likewise required for the inducible formation of FALCs. Thus, FALCs supported and coordinated the activation of innate B cells and T cells during serosal immune responses.


Assuntos
Inflamação/imunologia , Gordura Intra-Abdominal/imunologia , Linfócitos/imunologia , Tecido Linfoide/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Quimiocina CXCL13/genética , Quimiocina CXCL13/imunologia , Quimiocina CXCL13/metabolismo , Citometria de Fluxo , Expressão Gênica/imunologia , Inflamação/genética , Inflamação/metabolismo , Gordura Intra-Abdominal/metabolismo , Linfócitos/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Células Mieloides/imunologia , Células Mieloides/metabolismo , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Receptores do Fator de Necrose Tumoral/imunologia , Receptores do Fator de Necrose Tumoral/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Estromais/imunologia , Células Estromais/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
17.
Trends Immunol ; 45(7): 535-548, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38879436

RESUMO

Mammalian innate-like T cells (ILTCs), including mucosal-associated invariant T (MAIT), natural killer T (NKT), and γδ T cells, are abundant tissue-resident lymphocytes that have recently emerged as orchestrators of hepatic inflammation, tissue repair, and immune homeostasis. This review explores the involvement of different ILTC subsets in liver diseases. We explore the mechanisms underlying the pro- and anti-inflammatory effector functions of ILTCs in a context-dependent manner. We highlight latest findings regarding the dynamic interplay between ILTC functional subsets and other immune and parenchymal cells which may inform candidate immunomodulatory strategies to achieve improved clinical outcomes in liver diseases. We present new insights into how distinct gene expression programs in hepatic ILTCs are induced, maintained, and reprogrammed in a context- and disease stage-dependent manner.


Assuntos
Imunidade Inata , Hepatopatias , Humanos , Animais , Hepatopatias/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Matadoras Naturais/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fígado/imunologia
18.
Nature ; 600(7888): 302-307, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34759313

RESUMO

Small molecules derived from symbiotic microbiota critically contribute to intestinal immune maturation and regulation1. However, little is known about the molecular mechanisms that control immune development in the host-microbiota environment. Here, using a targeted lipidomic analysis and synthetic approach, we carried out a multifaceted investigation of immunomodulatory α-galactosylceramides from the human symbiont Bacteroides fragilis (BfaGCs). The characteristic terminal branching of BfaGCs is the result of incorporation of branched-chain amino acids taken up in the host gut by B. fragilis. A B. fragilis knockout strain that cannot metabolize branched-chain amino acids showed reduced branching in BfaGCs, and mice monocolonized with this mutant strain had impaired colonic natural killer T (NKT) cell regulation, implying structure-specific immunomodulatory activity. The sphinganine chain branching of BfaGCs is a critical determinant of NKT cell activation, which induces specific immunomodulatory gene expression signatures and effector functions. Co-crystal structure and affinity analyses of CD1d-BfaGC-NKT cell receptor complexes confirmed the interaction of BfaGCs as CD1d-restricted ligands. We present a structural and molecular-level paradigm of immunomodulatory control by interactions of endobiotic metabolites with diet, microbiota and the immune system.


Assuntos
Aminoácidos de Cadeia Ramificada/imunologia , Aminoácidos de Cadeia Ramificada/metabolismo , Bacteroides fragilis/metabolismo , Galactosilceramidas/imunologia , Galactosilceramidas/metabolismo , Microbioma Gastrointestinal/imunologia , Simbiose/imunologia , Aminoácidos de Cadeia Ramificada/química , Animais , Antígenos CD1d/imunologia , Bacteroides fragilis/genética , Humanos , Camundongos , Modelos Animais , Modelos Moleculares , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia
19.
Proc Natl Acad Sci U S A ; 121(29): e2403917121, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-38980903

RESUMO

Pancreatic ductal adenocarcinoma (PDA) is a potentially lethal disease lacking effective treatments. Its immunosuppressive tumor microenvironment (TME) allows it to evade host immunosurveillance and limits response to immunotherapy. Here, using the mouse KRT19-deficient (sgKRT19-edited) PDA model, we find that intratumoral accumulation of natural killer T (NKT) cells is required to establish an immunologically active TME. Mechanistically, intratumoral NKT cells facilitate type I interferon (IFN) production to initiate an antitumor adaptive immune response, and orchestrate the intratumoral infiltration of T cells, dendritic cells, natural killer cells, and myeloid-derived suppressor cells. At the molecular level, NKT cells promote the production of type I IFN through the interaction of their CD40L with CD40 on myeloid cells. To evaluate the therapeutic potential of these observations, we find that administration of folinic acid to mice bearing PDA increases NKT cells in the TME and improves their response to anti-PD-1 antibody treatment. In conclusion, NKT cells have an essential role in the immune response to mouse PDA and are potential targets for immunotherapy.


Assuntos
Carcinoma Ductal Pancreático , Células T Matadoras Naturais , Neoplasias Pancreáticas , Microambiente Tumoral , Animais , Camundongos , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Células T Matadoras Naturais/imunologia , Microambiente Tumoral/imunologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/patologia , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Imunoterapia/métodos , Camundongos Endogâmicos C57BL , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Humanos , Células Supressoras Mieloides/imunologia
20.
Proc Natl Acad Sci U S A ; 121(34): e2321686121, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39141352

RESUMO

To broadly measure the spectrum of cellular self-antigens for natural killer T cells (NKT), we developed a sensitive lipidomics system to analyze lipids trapped between CD1d and NKT T cell receptors (TCRs). We captured diverse antigen complexes formed in cells from natural endogenous lipids, with or without inducing endoplasmic reticulum (ER) stress. After separating protein complexes with no, low, or high CD1d-TCR interaction, we eluted lipids to establish the spectrum of self-lipids that facilitate this interaction. Although this unbiased approach identified fifteen molecules, they clustered into only two related groups: previously known phospholipid antigens and unexpected neutral lipid antigens. Mass spectrometry studies identified the neutral lipids as ceramides, deoxyceramides, and diacylglycerols, which can be considered headless lipids because they lack polar headgroups that usually form the TCR epitope. The crystal structure of the TCR-ceramide-CD1d complex showed how the missing headgroup allowed the TCR to predominantly contact CD1d, supporting a model of CD1d autoreactivity. Ceramide and related headless antigens mediated physiological TCR binding affinity, weak NKT cell responses, and tetramer binding to polyclonal human and mouse NKT cells. Ceramide and sphingomyelin are oppositely regulated components of the "sphingomyelin cycle" that are altered during apoptosis, transformation, and ER stress. Thus, the unique molecular link of ceramide to NKT cell response, along with the recent identification of sphingomyelin blockers of NKT cell activation, provide two mutually reinforcing links for NKT cell response to sterile cellular stress conditions.


Assuntos
Antígenos CD1d , Lipidômica , Células T Matadoras Naturais , Receptores de Antígenos de Linfócitos T , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/metabolismo , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Animais , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Camundongos , Lipidômica/métodos , Humanos , Autoantígenos/imunologia , Autoantígenos/metabolismo , Ceramidas/metabolismo , Ceramidas/imunologia , Lipídeos/química , Lipídeos/imunologia , Estresse do Retículo Endoplasmático/imunologia
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