Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 161
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Nat Immunol ; 22(9): 1163-1174, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426690

RESUMO

The immunosuppressive function of regulatory T (Treg) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of Treg cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from Treg cell paucity, highlighting a vital function of Treg cells in preventing fatal autoimmune inflammation. However, a major question remains whether Treg cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate Treg cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued Treg cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, Treg cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Fatores de Transcrição Forkhead/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Diferenciação Celular/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/genética , Homeostase/imunologia , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Resposta Inflamatória Sistêmica/patologia
2.
Science ; 373(6552)2021 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-34437125

RESUMO

Germinal centers (GCs) are the site of immunoglobulin somatic hypermutation and affinity maturation, processes essential to an effective antibody response. The formation of GCs has been studied in detail, but less is known about what leads to their regression and eventual termination, factors that ultimately limit the extent to which antibodies mature within a single reaction. We show that contraction of immunization-induced GCs is immediately preceded by an acute surge in GC-resident Foxp3+ T cells, attributed at least partly to up-regulation of the transcription factor Foxp3 by T follicular helper (TFH) cells. Ectopic expression of Foxp3 in TFH cells is sufficient to decrease GC size, implicating the natural up-regulation of Foxp3 by TFH cells as a potential regulator of GC lifetimes.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Fatores de Transcrição Forkhead/genética , Centro Germinativo/imunologia , Células T Auxiliares Foliculares/metabolismo , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Genes Codificadores dos Receptores de Linfócitos T , Centro Germinativo/citologia , Imunização , Imunofenotipagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Célula Única , Células T Auxiliares Foliculares/imunologia , Linfócitos T Reguladores/fisiologia , Regulação para Cima
3.
Sci Immunol ; 6(60)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117110

RESUMO

Effective antiviral immunity requires generation of T and B lymphocytes expressing the transcription factor T-bet, a regulator of type 1 inflammatory responses. Using T-bet expression as an endogenous marker for cells participating in a type 1 response, we report coordinated interactions of T-bet-expressing T and B lymphocytes on the basis of their dynamic colocalization at the T cell zone and B follicle boundary (T-B boundary) and germinal centers (GCs) during lung influenza infection. We demonstrate that the assembly of this circuit takes place in distinct anatomical niches within the draining lymph node, guided by CXCR3 that enables positioning of TH1 cells at the T-B boundary. The encounter of B and TH1 cells at the T-B boundary enables IFN-γ produced by the latter to induce IgG2c class switching. Within GCs, T-bet+ TFH cells represent a specialized stable sublineage required for GC growth but dispensable for IgG2c class switching. Our studies show that during respiratory viral infection, T-bet-expressing T and B lymphocytes form a circuit assembled in a spatiotemporally controlled manner that acts as a functional unit enabling a robust and coherent humoral response tailored for optimal antiviral immunity.

4.
Cell ; 184(13): 3361-3375, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34171319

RESUMO

Surface epithelia provide a critical barrier to the outside world. Upon a barrier breach, resident epithelial and immune cells coordinate efforts to control infections and heal tissue damage. Inflammation can etch lasting marks within tissues, altering features such as scope and quality of future responses. By remembering inflammatory experiences, tissues are better equipped to quickly and robustly respond to barrier breaches. Alarmingly, in disease states, memory may fuel the inflammatory fire. Here, we review the cellular communication networks in barrier tissues and the integration between tissue-resident and recruited immune cells and tissue stem cells underlying tissue adaptation to environmental stress.

5.
Cell ; 184(15): 3981-3997.e22, 2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34157301

RESUMO

A fraction of mature T cells can be activated by peripheral self-antigens, potentially eliciting host autoimmunity. We investigated homeostatic control of self-activated T cells within unperturbed tissue environments by combining high-resolution multiplexed and volumetric imaging with computational modeling. In lymph nodes, self-activated T cells produced interleukin (IL)-2, which enhanced local regulatory T cell (Treg) proliferation and inhibitory functionality. The resulting micro-domains reciprocally constrained inputs required for damaging effector responses, including CD28 co-stimulation and IL-2 signaling, constituting a negative feedback circuit. Due to these local constraints, self-activated T cells underwent transient clonal expansion, followed by rapid death ("pruning"). Computational simulations and experimental manipulations revealed the feedback machinery's quantitative limits: modest reductions in Treg micro-domain density or functionality produced non-linear breakdowns in control, enabling self-activated T cells to subvert pruning. This fine-tuned, paracrine feedback process not only enforces immune homeostasis but also establishes a sharp boundary between autoimmune and host-protective T cell responses.

6.
Cell Metab ; 33(5): 851-852, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33951469

RESUMO

Glycolysis supports effector T cell function but is detrimental to the immunosuppressive activity of regulatory T cells. In a recent issue of Nature, two papers address a role for glucose and lactate availability within the tumor microenvironment for the balance of pro- and anti-tumoral effects of T cells and the efficacy of neoadjuvant cancer immunotherapy.

7.
Immunity ; 54(5): 931-946.e11, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33838102

RESUMO

Activation of the STAT5 transcription factor downstream of the Interleukin-2 receptor (IL-2R) induces expression of Foxp3, a critical step in the differentiation of regulatory T (Treg) cells. Due to the pleiotropic effects of IL-2R signaling, it is unclear how STAT5 acts directly on the Foxp3 locus to promote its expression. Here, we report that IL-2 - STAT5 signaling converged on an enhancer (CNS0) during Foxp3 induction. CNS0 facilitated the IL-2 dependent CD25+Foxp3- precursor to Treg cell transition in the thymus. Its deficiency resulted in impaired Treg cell generation in neonates, which was partially mitigated with age. While the thymic Treg cell paucity caused by CNS0 deficiency did not result in autoimmunity on its own, it exacerbated autoimmune manifestations caused by disruption of the Aire gene. Thus, CNS0 enhancer activity ensures robust Treg cell differentiation early in postnatal life and cooperatively with other tolerance mechanisms minimizes autoimmunity.


Assuntos
Linhagem da Célula/imunologia , Fatores de Transcrição Forkhead/imunologia , Tolerância Imunológica/imunologia , Interleucina-2/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Elementos Facilitadores Genéticos/imunologia , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Masculino , Camundongos , Receptores de Interleucina-2/imunologia , Fator de Transcrição STAT5/imunologia , Transdução de Sinais/imunologia
8.
Mol Cell ; 81(11): 2477-2493.e10, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-33891860

RESUMO

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1+ progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Epigênese Genética/imunologia , Imunidade Celular , Coriomeningite Linfocítica/genética , Neoplasias/genética , Fatores de Transcrição/genética , Doença Aguda , Atlas como Assunto , Linfócitos T CD8-Positivos/classificação , Linfócitos T CD8-Positivos/patologia , Cromatina/química , Cromatina/imunologia , Doença Crônica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/patologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Neoplasias/imunologia , Neoplasias/patologia , Análise de Componente Principal , Análise de Célula Única , Fatores de Transcrição/classificação , Fatores de Transcrição/imunologia , Transcrição Genética , Transposases/genética , Transposases/metabolismo
10.
Science ; 371(6527): 405-410, 2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33479154

RESUMO

Infection triggers expansion and effector differentiation of T cells specific for microbial antigens in association with metabolic reprograming. We found that the glycolytic enzyme lactate dehydrogenase A (LDHA) is induced in CD8+ T effector cells through phosphoinositide 3-kinase (PI3K) signaling. In turn, ablation of LDHA inhibits PI3K-dependent phosphorylation of Akt and its transcription factor target Foxo1, causing defective antimicrobial immunity. LDHA deficiency cripples cellular redox control and diminishes adenosine triphosphate (ATP) production in effector T cells, resulting in attenuated PI3K signaling. Thus, nutrient metabolism and growth factor signaling are highly integrated processes, with glycolytic ATP serving as a rheostat to gauge PI3K-Akt-Foxo1 signaling in the control of T cell immunity. Such a bioenergetic mechanism for the regulation of signaling may explain the Warburg effect.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Glicólise , Lactato Desidrogenase 5/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Animais , Linfócitos T CD8-Positivos/enzimologia , Proteína Forkhead Box O1/metabolismo , Humanos , Lactato Desidrogenase 5/genética , Listeria monocytogenes , Listeriose/enzimologia , Listeriose/imunologia , Camundongos , Camundongos Mutantes , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Efeito Warburg em Oncologia
11.
J Exp Med ; 218(2)2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33095261

RESUMO

ST2, the receptor for the alarmin IL-33, is expressed by a subset of regulatory T (T reg) cells residing in nonlymphoid tissues, and these cells can potently expand upon provision of exogenous IL-33. Whether the accumulation and residence of T reg cells in tissues requires their cell-intrinsic expression of and signaling by ST2, or whether indirect IL-33 signaling acting on other cells suffices, has been a matter of contention. Here, we report that ST2 expression on T reg cells is largely dispensable for their accumulation and residence in nonlymphoid organs, including the visceral adipose tissue (VAT), even though cell-intrinsic sensing of IL-33 promotes type 2 cytokine production by VAT-residing T reg cells. In addition, we uncovered a novel ST2-dependent role for T reg cells in limiting the size of IL-17A-producing γδT cells in the CNS in a mouse model of neuroinflammation, experimental autoimmune encephalomyelitis (EAE). Finally, ST2 deficiency limited to T reg cells led to disease exacerbation in EAE.


Assuntos
Inflamação/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Neurônios/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/imunologia , Interleucina-33/imunologia , Masculino , Camundongos
12.
J Exp Med ; 218(4)2021 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-33373442

RESUMO

T cells increase cholesterol biosynthesis upon activation to generate substrates for cellular growth and proliferation. The ubiquitously expressed liver X receptor ß (LXRß) encoded by the Nr1h2 gene is a critical regulator of cholesterol homeostasis in mammalian cells; however, its cell-intrinsic role in T cell biology remains poorly understood. We report that ablation of LXRß in T cells leads to spontaneous T cell activation and T lymphocytopenia. Unexpectedly, analysis of mixed bone marrow chimeric mice revealed a cell-autonomous survival defect that reduced the fitness of LXRß-deficient effector T cells, suggesting that the heightened immune activation in mice harboring LXRß-deficient T cells was due to impaired regulatory T (T reg) cell functionality. Indeed, we found that single-copy deletion of Nr1h2 in T reg cells disrupted activated T reg cell metabolism and fitness and resulted in early-onset fatal autoimmune disease. Our study demonstrated an indispensable requirement for T reg cell-intrinsic LXRß function in immune homeostasis and provides a basis for immunological therapies through targeting of this receptor.


Assuntos
Doenças Autoimunes/imunologia , Homeostase/imunologia , Receptores X do Fígado/fisiologia , Ativação Linfocitária/genética , Linfócitos T Reguladores/imunologia , T-Linfocitopenia Idiopática CD4-Positiva/imunologia , Animais , Doenças Autoimunes/genética , Células Cultivadas , Colesterol/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Homeostase/genética , Receptores X do Fígado/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Quimera por Radiação/imunologia , Transdução de Sinais/genética , Linfócitos T Reguladores/metabolismo , T-Linfocitopenia Idiopática CD4-Positiva/genética
13.
Proc Natl Acad Sci U S A ; 117(52): 33446-33454, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318189

RESUMO

Reduced nutrient intake is a widely conserved manifestation of sickness behavior with poorly characterized effects on adaptive immune responses. During infectious challenges, naive T cells encountering their cognate antigen become activated and differentiate into highly proliferative effector T cells. Despite their evident metabolic shift upon activation, it remains unclear how effector T cells respond to changes in nutrient availability in vivo. Here, we show that spontaneous or imposed feeding reduction during infection decreases the numbers of splenic lymphocytes. Effector T cells showed cell-intrinsic responses dependent on the nuclear receptor Farnesoid X Receptor (FXR). Deletion of FXR in T cells prevented starvation-induced loss of lymphocytes and increased effector T cell fitness in nutrient-limiting conditions, but imparted greater weight loss to the host. FXR deficiency increased the contribution of glutamine and fatty acids toward respiration and enhanced cell survival under low-glucose conditions. Provision of glucose during anorexia of infection rescued effector T cells, suggesting that this sugar is a limiting nutrient for activated lymphocytes and that alternative fuel usage may affect cell survival in starved animals. Altogether, we identified a mechanism by which the host scales immune responses according to food intake, featuring FXR as a T cell-intrinsic sensor.


Assuntos
Comportamento Alimentar , Coriomeningite Linfocítica/imunologia , Receptores Citoplasmáticos e Nucleares/metabolismo , Linfócitos T/imunologia , Animais , Anorexia/virologia , Jejum , Coriomeningite Linfocítica/patologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/fisiologia , Camundongos Endogâmicos C57BL , Nutrientes/metabolismo , Baço/patologia , Transcrição Genética
14.
Immunity ; 53(5): 971-984.e5, 2020 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-33176163

RESUMO

Regulatory T (Treg) cell identity is defined by the lineage-specifying transcription factor (TF) Foxp3. Here we examined mechanisms of Foxp3 function by leveraging naturally occurring genetic variation in wild-derived inbred mice, which enables the identification of DNA sequence motifs driving epigenetic features. Chromatin accessibility, TF binding, and gene expression patterns in resting and activated subsets of Treg cells, conventional CD4 T cells, and cells expressing a Foxp3 reporter null allele revealed that the majority of Foxp3-dependent changes occurred at sites not bound by Foxp3. Chromatin accessibility of these indirect Foxp3 targets depended on the presence of DNA binding motifs for other TFs, including TCF1. Foxp3 expression correlated with decreased TCF1 and reduced accessibility of TCF1-bound chromatin regions. Deleting one copy of the Tcf7 gene recapitulated Foxp3-dependent negative regulation of chromatin accessibility. Thus, Foxp3 defines Treg cell identity in a largely indirect manner by fine-tuning the activity of other major chromatin remodeling TFs such as TCF1.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Autoimunidade/genética , Sítios de Ligação , Montagem e Desmontagem da Cromatina , Modelos Animais de Doenças , Epigênese Genética , Feminino , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica , Imuno-Histoquímica , Masculino , Camundongos , Motivos de Nucleotídeos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Ligação Proteica , Transativadores/metabolismo
15.
J Exp Med ; 217(11)2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-33057576

RESUMO

The advance of science is dependent upon collaboration, which does not have a visa attached to it. Indeed, over 40% of all American-based Nobel Prize winners are immigrants, and data from the National Science Foundation show that 49% of postdocs and 29% of science and engineering faculty in the US are foreign-born. However, restrictive new immigration policies in the US have left many scientists deeply concerned about their future and many American-based laboratories worried about attracting the best talent. At JEM, we're celebrating immigration by sharing the experiences of immigrant and nonimmigrant scientists on our editorial board. Alexander Rudensky and Jean-Laurent Casanova give their firsthand perspective on immigrating to the US, while Jedd Wolchok, Carl Nathan, David Holtzman, Susan Kaech, Lewis Lanier, and David Tuveson reflect on how immigration has affected their laboratories.


Assuntos
Emigrantes e Imigrantes/psicologia , Emigração e Imigração , Pesquisadores/psicologia , Humanos , Laboratórios , Liderança , Motivação , Pesquisa , Estados Unidos
16.
Immunity ; 53(4): 775-792.e9, 2020 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-33002412

RESUMO

Innate lymphoid cells (ILCs) are generated early during ontogeny and persist predominantly as tissue-resident cells. Here, we examined how ILCs are maintained and renewed within tissues. We generated a single cell atlas of lung ILC2s and found that Il18r1+ ILCs comprise circulating and tissue-resident ILC progenitors (ILCP) and effector-cells with heterogeneous expression of the transcription factors Tcf7 and Zbtb16, and CD103. Our analyses revealed a continuous differentiation trajectory from Il18r1+ ST2- ILCPs to Il18r- ST2+ ILC2s, which was experimentally validated. Upon helminth infection, recruited and BM-derived cells generated the entire spectrum of ILC2s in parabiotic and shield chimeric mice, consistent with their potential role in the renewal of tissue ILC2s. Our findings identify local ILCPs and reveal ILCP in situ differentiation and tissue adaptation as a mechanism of ILC maintenance and phenotypic diversification. Local niches, rather than progenitor origin, or the developmental window during ontogeny, may dominantly imprint ILC phenotypes in adult tissues.


Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Células Progenitoras Linfoides/imunologia , Animais , Diferenciação Celular/imunologia , Células Cultivadas , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-18/imunologia , Pulmão/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Proteína com Dedos de Zinco da Leucemia Promielocítica/imunologia , Transdução de Sinais/imunologia , Análise de Célula Única/métodos , Fator 1 de Transcrição de Linfócitos T/imunologia , Fatores de Transcrição/imunologia
18.
Nature ; 581(7809): 475-479, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32461639

RESUMO

Intestinal health relies on the immunosuppressive activity of CD4+ regulatory T (Treg) cells1. Expression of the transcription factor Foxp3 defines this lineage, and can be induced extrathymically by dietary or commensal-derived antigens in a process assisted by a Foxp3 enhancer known as conserved non-coding sequence 1 (CNS1)2-4. Products of microbial fermentation including butyrate facilitate the generation of peripherally induced Treg (pTreg) cells5-7, indicating that metabolites shape the composition of the colonic immune cell population. In addition to dietary components, bacteria modify host-derived molecules, generating a number of biologically active substances. This is epitomized by the bacterial transformation of bile acids, which creates a complex pool of steroids8 with a range of physiological functions9. Here we screened the major species of deconjugated bile acids for their ability to potentiate the differentiation of pTreg cells. We found that the secondary bile acid 3ß-hydroxydeoxycholic acid (isoDCA) increased Foxp3 induction by acting on dendritic cells (DCs) to diminish their immunostimulatory properties. Ablating one receptor, the farnesoid X receptor, in DCs enhanced the generation of Treg cells and imposed a transcriptional profile similar to that induced by isoDCA, suggesting an interaction between this bile acid and nuclear receptor. To investigate isoDCA in vivo, we took a synthetic biology approach and designed minimal microbial consortia containing engineered Bacteroides strains. IsoDCA-producing consortia increased the number of colonic RORγt-expressing Treg cells in a CNS1-dependent manner, suggesting enhanced extrathymic differentiation.


Assuntos
Bactérias/metabolismo , Ácidos e Sais Biliares/química , Ácidos e Sais Biliares/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Sequência de Aminoácidos , Animais , Bacteroides/metabolismo , Colo/microbiologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Fermentação , Microbioma Gastrointestinal , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Consórcios Microbianos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo
19.
Science ; 367(6475): 247-248, 2020 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-31949067
20.
Cell ; 179(4): 846-863.e24, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31668803

RESUMO

Dendritic cells (DCs) play a critical role in orchestrating adaptive immune responses due to their unique ability to initiate T cell responses and direct their differentiation into effector lineages. Classical DCs have been divided into two subsets, cDC1 and cDC2, based on phenotypic markers and their distinct abilities to prime CD8 and CD4 T cells. While the transcriptional regulation of the cDC1 subset has been well characterized, cDC2 development and function remain poorly understood. By combining transcriptional and chromatin analyses with genetic reporter expression, we identified two principal cDC2 lineages defined by distinct developmental pathways and transcriptional regulators, including T-bet and RORγt, two key transcription factors known to define innate and adaptive lymphocyte subsets. These novel cDC2 lineages were characterized by distinct metabolic and functional programs. Extending our findings to humans revealed conserved DC heterogeneity and the presence of the newly defined cDC2 subsets in human cancer.


Assuntos
Diferenciação Celular/genética , Linhagem da Célula/genética , Heterogeneidade Genética , Neoplasias/imunologia , Imunidade Adaptativa/genética , Animais , Diferenciação Celular/imunologia , Cromatina/genética , Células Dendríticas/imunologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Imunidade Inata/genética , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Camundongos , Neoplasias/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcrição Genética/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...