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1.
Nat Immunol ; 25(2): 330-342, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38172260

RESUMO

Antibody-secreting plasma cells (PCs) are generated in secondary lymphoid organs but are reported to reside in an emerging range of anatomical sites. Analysis of the transcriptome of different tissue-resident (Tr)PC populations revealed that they each have their own transcriptional signature indicative of functional adaptation to the host tissue environment. In contrast to expectation, all TrPCs were extremely long-lived, regardless of their organ of residence, with longevity influenced by intrinsic factors like the immunoglobulin isotype. Analysis at single-cell resolution revealed that the bone marrow is unique in housing a compendium of PCs generated all over the body that retain aspects of the transcriptional program indicative of their tissue of origin. This study reveals that extreme longevity is an intrinsic property of TrPCs whose transcriptome is imprinted by signals received both at the site of induction and within the tissue of residence.


Assuntos
Medula Óssea , Plasmócitos , Células da Medula Óssea
2.
Nat Immunol ; 25(3): 496-511, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38356058

RESUMO

Visceral adipose tissue (VAT) is an energy store and endocrine organ critical for metabolic homeostasis. Regulatory T (Treg) cells restrain inflammation to preserve VAT homeostasis and glucose tolerance. Here, we show that the VAT harbors two distinct Treg cell populations: prototypical serum stimulation 2-positive (ST2+) Treg cells that are enriched in males and a previously uncharacterized population of C-X-C motif chemokine receptor 3-positive (CXCR3+) Treg cells that are enriched in females. We show that the transcription factors GATA-binding protein 3 and peroxisome proliferator-activated receptor-γ, together with the cytokine interleukin-33, promote the differentiation of ST2+ VAT Treg cells but repress CXCR3+ Treg cells. Conversely, the differentiation of CXCR3+ Treg cells is mediated by the cytokine interferon-γ and the transcription factor T-bet, which also antagonize ST2+ Treg cells. Finally, we demonstrate that ST2+ Treg cells preserve glucose homeostasis, whereas CXCR3+ Treg cells restrain inflammation in lean VAT and prevent glucose intolerance under high-fat diet conditions. Overall, this study defines two molecularly and developmentally distinct VAT Treg cell types with unique context- and sex-specific functions.


Assuntos
Proteína 1 Semelhante a Receptor de Interleucina-1 , Linfócitos T Reguladores , Feminino , Masculino , Humanos , Gordura Intra-Abdominal , Citocinas , Inflamação , Glucose
3.
Nat Immunol ; 22(4): 434-448, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649580

RESUMO

T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.


Assuntos
Infecções por Arenaviridae/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Memória Imunológica , Linfonodos/metabolismo , Células Precursoras de Linfócitos T/metabolismo , Receptores CXCR3/metabolismo , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Linhagem da Célula , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Quimiotaxia de Leucócito , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Ligantes , Linfonodos/imunologia , Linfonodos/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/virologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR3/genética , Transdução de Sinais , Nicho de Células-Tronco , Células Estromais/imunologia , Células Estromais/metabolismo
4.
Nat Immunol ; 22(7): 851-864, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099918

RESUMO

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.


Assuntos
Anticorpos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-33/farmacologia , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
5.
Immunity ; 57(5): 1037-1055.e6, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38593796

RESUMO

Memory B cells (MBCs) are key providers of long-lived immunity against infectious disease, yet in chronic viral infection, they do not produce effective protection. How chronic viral infection disrupts MBC development and whether such changes are reversible remain unknown. Through single-cell (sc)ATAC-seq and scRNA-seq during acute versus chronic lymphocytic choriomeningitis viral infection, we identified a memory subset enriched for interferon (IFN)-stimulated genes (ISGs) during chronic infection that was distinct from the T-bet+ subset normally associated with chronic infection. Blockade of IFNAR-1 early in infection transformed the chromatin landscape of chronic MBCs, decreasing accessibility at ISG-inducing transcription factor binding motifs and inducing phenotypic changes in the dominating MBC subset, with a decrease in the ISG subset and an increase in CD11c+CD80+ cells. However, timing was critical, with MBCs resistant to intervention at 4 weeks post-infection. Together, our research identifies a key mechanism to instruct MBC identity during viral infection.


Assuntos
Epigênese Genética , Interferon Tipo I , Coriomeningite Linfocítica , Vírus da Coriomeningite Linfocítica , Células B de Memória , Animais , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Camundongos , Vírus da Coriomeningite Linfocítica/imunologia , Células B de Memória/imunologia , Camundongos Endogâmicos C57BL , Receptor de Interferon alfa e beta/genética , Memória Imunológica/imunologia , Doença Crônica , Subpopulações de Linfócitos B/imunologia , Análise de Célula Única
6.
Immunity ; 55(10): 1843-1855.e6, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36108634

RESUMO

To optimize immunity to pathogens, B lymphocytes generate plasma cells with functionally diverse antibody isotypes. By lineage tracing single cells within differentiating B cell clones, we identified the heritability of discrete fate controlling mechanisms to inform a general mathematical model of B cell fate regulation. Founder cells highly influenced clonal plasma-cell fate, whereas class switch recombination (CSR) was variegated within clones. In turn, these CSR patterns resulted from independent all-or-none expression of both activation-induced cytidine deaminase (AID) and IgH germline transcription (GLT), with the latter being randomly re-expressed after each cell division. A stochastic model premised on these molecular transition rules accurately predicted antibody switching outcomes under varied conditions in vitro and during an immune response in vivo. Thus, the generation of functionally diverse antibody types follows rules of autonomous cellular programming that can be adapted and modeled for the rational control of antibody classes for potential therapeutic benefit.


Assuntos
Switching de Imunoglobulina , Recombinação Genética , Linfócitos B , Citidina Desaminase/genética , Citidina Desaminase/metabolismo , Switching de Imunoglobulina/genética , Isotipos de Imunoglobulinas/genética , Isotipos de Imunoglobulinas/metabolismo
7.
Immunity ; 55(3): 423-441.e9, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35139355

RESUMO

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation. Instead, caspase-8 reduced pro-survival BCL-2 transcription and increased inducible nitric oxide synthase (iNOS), thus facilitating BAX and BAK signaling. IFNγ-primed, TLR-induced macrophage killing required iNOS, which licensed apoptotic caspase-8 activity and reduced the BAX and BAK inhibitors, A1 and MCL-1. The deletion of iNOS or caspase-8 limited SARS-CoV-2-induced disease in mice, while caspase-8 caused lethality independent of iNOS in a model of hemophagocytic lymphohistiocytosis. These findings reveal that iNOS selectively licenses programmed cell death, which may explain how nitric oxide impacts disease severity in SARS-CoV-2 infection and other iNOS-associated inflammatory conditions.


Assuntos
COVID-19/imunologia , Caspase 8/metabolismo , Interferon gama/metabolismo , Linfo-Histiocitose Hemofagocítica/imunologia , Macrófagos/imunologia , Mitocôndrias/metabolismo , SARS-CoV-2/fisiologia , Animais , Caspase 8/genética , Células Cultivadas , Citotoxicidade Imunológica , Humanos , Interferon gama/genética , Ativação de Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/metabolismo , Moléculas com Motivos Associados a Patógenos/imunologia , Transdução de Sinais , Proteína Killer-Antagonista Homóloga a bcl-2/genética , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
8.
Nat Immunol ; 24(2): 205-206, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36658242
11.
Cell ; 150(6): 1249-63, 2012 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-22980984

RESUMO

A defining feature of vertebrate immunity is the acquisition of immunological memory, which confers enhanced protection against pathogens by mechanisms that are incompletely understood. Here, we compared responses by virus-specific naive T cells (T(N)) and central memory T cells (T(CM)) to viral antigen challenge in lymph nodes (LNs). In steady-state LNs, both T cell subsets localized in the deep T cell area and interacted similarly with antigen-presenting dendritic cells. However, upon entry of lymph-borne virus, only T(CM) relocalized rapidly and efficiently toward the outermost LN regions in the medullary, interfollicular, and subcapsular areas where viral infection was initially confined. This rapid peripheralization was coordinated by a cascade of cytokines and chemokines, particularly ligands for T(CM)-expressed CXCR3. Consequently, in vivo recall responses to viral infection by CXCR3-deficient T(CM) were markedly compromised, indicating that early antigen detection afforded by intranodal chemokine guidance of T(CM) is essential for efficient antiviral memory.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Quimiocina CXCL9/imunologia , Células Dendríticas/imunologia , Interferon gama/imunologia , Linfonodos/citologia , Vírus da Coriomeningite Linfocítica , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores CXCR3/imunologia , Células Estromais/imunologia , Vírus da Estomatite Vesicular Indiana
12.
Immunol Rev ; 306(1): 76-92, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34882817

RESUMO

The lymph node plays a critical role in mounting an adaptive immune response to infection, clearance of foreign pathogens, and cancer immunosurveillance. Within this complex structure, intranodal migration is vital for CD8+ T cell activation and differentiation. Combining tissue clearing and volumetric light sheet fluorescent microscopy of intact lymph nodes has allowed us to explore the spatial regulation of T cell fates. This has determined that short-lived effector (TSLEC ) are imprinted in peripheral lymph node interfollicular regions, due to CXCR3 migration. In contrast, stem-like memory cell (TSCM ) differentiation is determined in the T cell paracortex. Here, we detail the inflammatory and chemokine regulators of spatially restricted T cell differentiation, with a focus on how to promote TSCM . We propose a default pathway for TSCM differentiation due to CCR7-directed segregation of precursors away from the inflammatory effector niche. Although volumetric imaging has revealed the consequences of intranodal migration, we still lack knowledge of how this is orchestrated within a complex chemokine environment. Toward this goal, we highlight the potential of combining microfluidic chambers with pre-determined complexity and subcellular resolution microscopy.


Assuntos
Linfócitos T CD8-Positivos , Memória Imunológica , Diferenciação Celular , Quimiocinas/metabolismo , Humanos , Linfonodos , Ativação Linfocitária
13.
PLoS Pathog ; 19(9): e1011666, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37733817

RESUMO

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80-90%) against lethal murine salmonellosis, in comparison with a moderately protective (40-50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity.


Assuntos
Linfócitos T CD4-Positivos , Infecções por Salmonella , Camundongos , Animais , Monócitos , Vacinas Atenuadas , Inflamação
14.
Nat Immunol ; 14(4): 389-95, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23455676

RESUMO

NKp46+ innate lymphoid cells (ILCs) serve important roles in regulating the intestinal microbiota and defense against pathogens. Whether NKp46+ ILCs arise directly from lymphoid tissue-inducer (LTi) cells or represent a separate lineage remains controversial. We report here that the transcription factor T-bet (encoded by Tbx21) was essential for the development of NKp46+ ILCs but not of LTi cells or nuocytes. Deficiency in interleukin 22 (IL-22)-producing NKp46+ ILCs resulted in greater susceptibility of Tbx21-/- mice to intestinal infection. Haploinsufficient T-bet expression resulted in lower expression of the signaling molecule Notch, and Notch signaling was necessary for the transition of LTi cells into NKp46+ ILCs. Furthermore, NKp46+ ILCs differentiated solely from the CD4- LTi population, not the CD4+ LTi population. Our results pinpoint the regulation of Notch signaling by T-bet as a distinct molecular pathway that guides the development of NKp46+ ILCs.


Assuntos
Antígenos Ly/metabolismo , Imunidade Inata , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Receptor 1 Desencadeador da Citotoxicidade Natural/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Citrobacter rodentium/imunologia , Infecções por Enterobacteriaceae/imunologia , Subpopulações de Linfócitos/citologia , Camundongos , Camundongos Knockout , Proteínas com Domínio T/genética
15.
Immunol Rev ; 300(1): 203-219, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33586207

RESUMO

The relationship between the extrinsic environment and the internal transcriptional network is circular. Naive T cells first engage with antigen-presenting cells to set transcriptional differentiation networks in motion. In turn, this regulates specific chemokine receptors that direct migration into distinct lymph node niches. Movement into these regions brings newly activated T cells into contact with accessory cells and cytokines that reinforce the differentiation programming to specify T cell function. We and others have observed similarities in the transcriptional networks that specify both CD4+ T follicular helper (TFH ) cells and CD8+ central memory stem-like (TSCM ) cells. Here, we compare and contrast the current knowledge for these shared differentiation programs, compared to their effector counterparts, CD4+ T-helper 1 (TH1 ) and CD8+ short-lived effector (TSLEC ) cells. Understanding the interplay between cellular interactions and transcriptional programming is essential to harness T cell differentiation that is fit for purpose; to stimulate potent T cell effector function for the elimination of chronic infection and cancer; or to amplify the formation of humoral immunity and longevity of cellular memory to prevent infectious diseases.


Assuntos
Comunicação Celular , Linfócitos T , Células Apresentadoras de Antígenos , Diferenciação Celular , Receptores de Quimiocinas , Linfócitos T Auxiliares-Indutores
16.
Immunol Cell Biol ; 101(4): 345-357, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-36710659

RESUMO

The transcription factor Myc is critically important in driving cell proliferation, a function that is frequently dysregulated in cancer. To avoid this dysregulation Myc is tightly controlled by numerous layers of regulation. One such layer is the use of distal regulatory enhancers to drive Myc expression. Here, using chromosome conformation capture to examine B cells of the immune system in the first hours after their activation, we reveal a previously unidentified enhancer of Myc. The interactivity of this enhancer coincides with a dramatic, but discrete, spike in Myc expression 3 h post-activation. However, genetic deletion of this region, has little impact on Myc expression, Myc protein level or in vitro and in vivo cell proliferation. Examination of the enhancer deleted regulatory landscape suggests that enhancer redundancy likely sustains Myc expression. This work highlights not only the importance of temporally examining enhancers, but also the complexity and dynamics of the regulation of critical genes such as Myc.


Assuntos
Elementos Facilitadores Genéticos , Genes myc , Elementos Facilitadores Genéticos/genética , Fatores de Transcrição/metabolismo , Regulação da Expressão Gênica , Regiões Promotoras Genéticas
17.
Immunol Rev ; 289(1): 101-114, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977199

RESUMO

A fundamental question in immunology is how cells decide between distinct T helper, effector or memory differentiation fates. These decisions are paramount to overcome infection and establish long-lasting protection. The impact of cell location for the determination of T-cell fate decisions is an emerging field. This review will discuss our current understanding of the migration path that T cells follow, within draining lymph nodes, to steer differentiation down distinct paths of either effector or memory fates. In particular, the regulation of migration and cellular encounters mediated by the chemokine receptor CXCR3 and its ligands will be discussed. The combination of increased antigen density and unique cellular partners play a central role in facilitating the site-specific differentiation of effector T cells, within the interfollicular regions of draining lymph nodes. Recent advances have applied this knowledge to optimize vaccine design to target antigen to lymph nodes. Increased understanding of the regulation of CXCR3 ligands and how T cells integrate multiple chemokine cues will help further progress in this field and allow additional applications to direct cell differentiation outside the lymph node, to enhance memory residency in peripheral tissues and effector anti-tumor responses.


Assuntos
Quimiocinas/metabolismo , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Humanos , Imunomodulação , Ativação Linfocitária
18.
Immunol Cell Biol ; 100(5): 312-322, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35233830

RESUMO

The chemokine receptor CXCR3 is expressed on immune cells to co-ordinate lymphocyte activation and migration. CXCR3 binds three chemokine ligands, CXCL9, CXCL10 and CXCL11. These ligands display distinct expression patterns and ligand signaling biases; however, how each ligand functions individually and collaboratively is incompletely understood. CXCL9 and CXCL10 are considered pro-inflammatory chemokines during viral infection, while CXCL11 may induce a tolerizing state. The investigation of the individual role of CXCL11 in vivo has been hampered as C57BL/6 mice carry several mutations that result in a null allele. Here, CRISPR/Cas9 was used to correct these mutations on a C57BL/6 background. It was validated that CXCL11KI mice expressed CXCL11 protein in dendritic cells, spleen and lung. CXCL11KI mice were largely phenotypically indistinguishable from C57BL/6 mice, both at steady-state and during two models of viral infection. While CXCL11 expression did not modify acute antiviral responses, this study provides a new tool to understand the role of CXCL11 in other experimental settings.


Assuntos
Quimiocina CXCL10 , Quimiocina CXCL11/metabolismo , Viroses , Animais , Quimiocina CXCL10/genética , Quimiocina CXCL11/genética , Quimiocina CXCL9/genética , Quimiocina CXCL9/metabolismo , Imunidade , Ligantes , Camundongos , Camundongos Endogâmicos C57BL
19.
Immunity ; 37(6): 1091-103, 2012 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-23123063

RESUMO

Differentiation of naive CD4(+) T cells into T helper (Th) cells is a defining event in adaptive immunity. The cytokines and transcription factors that control Th cell differentiation are understood, but it is not known how this process is orchestrated within lymph nodes (LNs). Here we have shown that the CXCR3 chemokine receptor was required for optimal generation of interferon-γ (IFN-γ)-secreting Th1 cells in vivo. By using a CXCR3 ligand reporter mouse, we found that stromal cells predominately expressed the chemokine ligand CXCL9 whereas hematopoietic cells expressed CXCL10 in LNs. Dendritic cell (DC)-derived CXCL10 facilitated T cell-DC interactions in LNs during T cell priming while both chemokines guided intranodal positioning of CD4(+) T cells to interfollicular and medullary zones. Thus, different chemokines acting on the same receptor can function locally to facilitate DC-T cell interactions and globally to influence intranodal positioning, and both functions contribute to Th1 cell differentiation.


Assuntos
Diferenciação Celular/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Receptores CXCR3/metabolismo , Células Th1/citologia , Células Th1/imunologia , Animais , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Quimiocina CXCL9/genética , Quimiocina CXCL9/imunologia , Quimiocinas CXC/genética , Quimiocinas CXC/imunologia , Citocinas/biossíntese , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação da Expressão Gênica , Interferon gama/biossíntese , Ligantes , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Camundongos , Camundongos Transgênicos , Ligação Proteica , Receptores CXCR3/genética
20.
Proc Natl Acad Sci U S A ; 114(20): 5225-5230, 2017 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-28461487

RESUMO

The lymphoid tissue that drains the upper respiratory tract represents an important induction site for cytotoxic T lymphocyte (CTL) immunity to airborne pathogens and intranasal vaccines. Here, we investigated the role of the nasal-associated lymphoid tissues (NALTs), which are mucosal-associated lymphoid organs embedded in the submucosa of the nasal passage, in the initial priming and recall expansion of CD8+ T cells following an upper respiratory tract infection with a pathogenic influenza virus and immunization with a live attenuated influenza virus vaccine. Whereas NALTs served as the induction site for the recall expansion of memory CD8+ T cells following influenza virus infection or vaccination, they failed to support activation of naïve CD8+ T cells. Strikingly, NALTs, unlike other lymphoid tissues, were not routinely surveyed during the steady state by circulating T cells. The selective recruitment of memory T cells into these lymphoid structures occurred in response to infection-induced elevation of the chemokine CXCL10, which attracted CXCR3+ memory CD8+ T cells. These results have significant implications for intranasal vaccines, which deliver antigen to mucosal-associated lymphoid tissue and aim to elicit protective CTL-mediated immunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunidade nas Mucosas/imunologia , Linfócitos T Citotóxicos/imunologia , Administração Intranasal , Animais , Imunização , Vírus da Influenza A/imunologia , Vacinas contra Influenza/imunologia , Linfonodos/fisiologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mucosa Nasal/metabolismo , Mucosa Nasal/fisiologia , Infecções por Orthomyxoviridae/imunologia , Infecções Respiratórias , Vacinação
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