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1.
Methods Protoc ; 7(2)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38525778

RESUMO

The generation of bone-marrow-derived dendritic cells is a widely used approach in immunological research to study antigen processing and presentation, as well as T-cell activation responses. However, the initial step of isolating the bone marrow can be time-consuming, especially when larger numbers of precursor cells are required. Here, we assessed whether an accelerated bone marrow isolation method using centrifugation is suitable for the differentiation of FMS-like tyrosine kinase 3 ligand-driven dendritic cells. Compared to the conventional flushing method, the centrifugation-based isolation method resulted in a similar bone marrow cell yield on Day 0, increased cell numbers by Day 8, similar proportions of dendritic cell subsets, and consequently a higher number of type 1 conventional dendritic cells (cDC1) from the culture. Although the primary purpose of this method of optimization was to improve experimental efficiency and increase the output of cDC1s, the protocol is also compatible with the differentiation of other dendritic cell subsets such as cDC2 and plasmacytoid dendritic cells, with an improved output cell count and a consistent phenotype.

2.
Immunol Cell Biol ; 2023 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-37982599

RESUMO

Scientific outreach activities play an important role in disseminating knowledge, connecting the general public to research and breaking down scientific skepticism barriers. However, the vision-impaired community is often disadvantaged when the most common audio-visual approach of scientific communication is applied. Here we integrated tactile clues in the scientific communication of immune processes involved in the autoimmune skin disease psoriasis. We fostered the involvement of the vision-impaired community through interactive experiences, including tactile scientific origami art, a haptic poster and wood-carved molecular models. Readily accessible science communication that engages a number of senses is a critical step toward making science more inclusive and engaging for individuals with a wide range of sensory abilities. The approach of the 2023 Monash Sensory Science exhibition aligns with the principles of equity, diversity and inclusion and helps to empower a more informed and scientifically literate public.

3.
J Biol Chem ; 299(7): 104930, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37330172

RESUMO

Psoriasis is a chronic skin disease characterized by hyperproliferative epidermal lesions infiltrated by autoreactive T cells. Individuals expressing the human leukocyte antigen (HLA) C∗06:02 allele are at highest risk for developing psoriasis. An autoreactive T cell clone (termed Vα3S1/Vß13S1) isolated from psoriatic plaques is selective for HLA-C∗06:02, presenting a peptide derived from the melanocyte-specific autoantigen ADAMTSL5 (VRSRRCLRL). Here we determine the crystal structure of this psoriatic TCR-HLA-C∗06:02 ADAMTSL5 complex with a stabilized peptide. Docking of the TCR involves an extensive complementary charge network formed between negatively charged TCR residues interleaving with exposed arginine residues from the self-peptide and the HLA-C∗06:02 α1 helix. We probed these interactions through mutagenesis and activation assays. The charged interface spans the polymorphic region of the C1/C2 HLA group. Notably the peptide-binding groove of HLA-C∗06:02 appears exquisitely suited for presenting highly charged Arg-rich epitopes recognized by this acidic psoriatic TCR. Overall, we provide a structural basis for understanding the engagement of melanocyte antigen-presenting cells by a TCR implicated in psoriasis while simultaneously expanding our knowledge of how TCRs engage HLA-C.


Assuntos
Antígenos HLA-C , Psoríase , Humanos , Eletricidade Estática , Peptídeos/química , Psoríase/patologia , Receptores de Antígenos de Linfócitos T/genética , Proteínas ADAMTS
4.
Comput Struct Biotechnol J ; 21: 1678-1687, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36890882

RESUMO

Immunopeptidomics has made tremendous contributions to our understanding of antigen processing and presentation, by identifying and quantifying antigenic peptides presented on the cell surface by Major Histocompatibility Complex (MHC) molecules. Large and complex immunopeptidomics datasets can now be routinely generated using Liquid Chromatography-Mass Spectrometry techniques. The analysis of this data - often consisting of multiple replicates/conditions - rarely follows a standard data processing pipeline, hindering the reproducibility and depth of analysis of immunopeptidomic data. Here, we present Immunolyser, an automated pipeline designed to facilitate computational analysis of immunopeptidomic data with a minimal initial setup. Immunolyser brings together routine analyses, including peptide length distribution, peptide motif analysis, sequence clustering, peptide-MHC binding affinity prediction, and source protein analysis. Immunolyser provides a user-friendly and interactive interface via its webserver and is freely available for academic purposes at https://immunolyser.erc.monash.edu/. The open-access source code can be downloaded at our GitHub repository: https://github.com/prmunday/Immunolyser. We anticipate that Immunolyser will serve as a prominent computational pipeline to facilitate effortless and reproducible analysis of immunopeptidomic data.

5.
J Clin Invest ; 131(21)2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34428180

RESUMO

While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically engineered major histocompatibility complex class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway, and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly recognized pMHC epitopes and identified 17 strongly immunogenic H-2Kb-associated peptides recognized by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognized by BALB/c (H-2d) mice. As few as 5 different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Peptídeos/imunologia , Transplante de Pele , Tolerância ao Transplante/imunologia , Aloenxertos , Animais , Camundongos , Camundongos Endogâmicos BALB C
6.
Immunol Cell Biol ; 99(8): 894-906, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34080230

RESUMO

Regulatory T cells (Tregs) play a critical role in immune regulation and peripheral tolerance. While different types of Tregs have been identified in both mice and humans, much of our understanding about how these cells maintain immune homeostasis is derived from animal models. In this study, we examined two distinct human lymphoid organs to understand how repeated exposure to infections at the mucosal surface influences the phenotype and tissue localization of Tregs. We show that while Tregs in both tonsils and spleen express a tissue-resident phenotype, they accumulate in greater numbers in tonsils. Tonsillar-resident Tregs exhibit a highly suppressive phenotype with significantly increased expression of CD39, ICOS and CTLA-4 compared with their counterparts in circulation or in the spleen. Functionally, resident Tregs are able effectively to suppress T cell proliferation. We further demonstrate that tonsillar-resident Tregs share key features of T follicular helper cells. Spatial analysis reveals that the vast majority of resident Tregs are localized at the border of the T-zone and B cell follicle, as well as within the lymphocyte pockets enriched with resident memory T cells. Together our findings suggest that resident Tregs are strategically co-localized to maintain immune homeostasis at sites of recurrent inflammation.


Assuntos
Ativação Linfocitária , Linfócitos T Reguladores , Animais , Linfócitos B , Humanos , Camundongos , Fenótipo
7.
J Exp Med ; 218(6)2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-33914023

RESUMO

Tissue-resident memory T cells (TRM cells) are key elements of tissue immunity. Here, we investigated the role of the regulator of T cell receptor and cytokine signaling, Ptpn2, in the formation and function of TRM cells in skin. Ptpn2-deficient CD8+ T cells displayed a marked defect in generating CD69+ CD103+ TRM cells in response to herpes simplex virus type 1 (HSV-1) skin infection. This was accompanied by a reduction in the proportion of KLRG1- memory precursor cells and a transcriptional bias toward terminal differentiation. Of note, forced expression of KLRG1 was sufficient to impede TRM cell formation. Normalizing memory precursor frequencies by transferring equal numbers of KLRG1- cells restored TRM generation, demonstrating that Ptpn2 impacted skin seeding with precursors rather than downstream TRM cell differentiation. Importantly, Ptpn2-deficient TRM cells augmented skin autoimmunity but also afforded superior protection from HSV-1 infection. Our results emphasize that KLRG1 repression is required for optimal TRM cell formation in skin and reveal an important role of Ptpn2 in regulating TRM cell functionality.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Lectinas Tipo C/imunologia , Proteína Tirosina Fosfatase não Receptora Tipo 2/imunologia , Receptores Imunológicos/imunologia , Animais , Autoimunidade/imunologia , Feminino , Herpes Simples/imunologia , Herpesvirus Humano 1/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Pele/imunologia
8.
Proteomics ; 21(17-18): e2100036, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33811468

RESUMO

SARS-CoV-2 has caused a significant ongoing pandemic worldwide. A number of studies have examined the T cell mediated immune responses against SARS-CoV-2, identifying potential T cell epitopes derived from the SARS-CoV-2 proteome. Such studies will aid in identifying targets for vaccination and immune monitoring. In this study, we applied tandem mass spectrometry and proteomic techniques to a library of ∼40,000 synthetic peptides, in order to generate a large dataset of SARS-CoV-2 derived peptide MS/MS spectra. On this basis, we built an online knowledgebase, termed virusMS (https://virusms.erc.monash.edu/), to document, annotate and analyse these synthetic peptides and their spectral information. VirusMS incorporates a user-friendly interface to facilitate searching, browsing and downloading the database content. Detailed annotations of the peptides, including experimental information, peptide modifications, predicted peptide-HLA (human leukocyte antigen) binding affinities, and peptide MS/MS spectral data, are provided in virusMS.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , Peptídeos , Proteômica , Espectrometria de Massas em Tandem
9.
Nat Commun ; 11(1): 1114, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111837

RESUMO

Little is known regarding lymph node (LN)-homing of immune cells via afferent lymphatics. Here, we show, using a photo-convertible Dendra-2 reporter, that recently activated CD4 T cells enter downstream LNs via afferent lymphatics at high frequencies. Intra-lymphatic immune cell transfer and live imaging data further show that activated T cells come to an instantaneous arrest mediated passively by the mechanical 3D-sieve barrier of the LN subcapsular sinus (SCS). Arrested T cells subsequently migrate randomly on the sinus floor independent of both chemokines and integrins. However, chemokine receptors are imperative for guiding cells out of the SCS, and for their subsequent directional translocation towards the T cell zone. By contrast, integrins are dispensable for LN homing, yet still contribute by increasing the dwell time within the SCS and by potentially enhancing T cell sensing of chemokine gradients. Together, these findings provide fundamental insights into mechanisms that control homing of lymph-derived immune cells.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Movimento Celular/imunologia , Quimiocinas/metabolismo , Integrinas/metabolismo , Linfonodos/fisiologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Endotélio Linfático/fisiologia , Integrinas/genética , Linfa/citologia , Linfonodos/citologia , Ativação Linfocitária , Camundongos , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Receptores de Retorno de Linfócitos/metabolismo
11.
PLoS One ; 14(2): e0210495, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30742629

RESUMO

Tissue-resident CD8+ memory T (TRM) cells are immune cells that permanently reside at tissue sites where they play an important role in providing rapid protection against reinfection. They are not only phenotypically and functionally distinct from their circulating memory counterparts, but also exhibit a unique transcriptional profile. To date, the local tissue signals required for their development and long-term residency are not well understood. So far, the best-characterised tissue-derived signal is transforming growth factor-ß (TGF-ß), which has been shown to promote the development of these cells within tissues. In this study, we aimed to determine to what extent the transcriptional signatures of TRM cells from multiple tissues reflects TGF-ß imprinting. We activated murine CD8+ T cells, stimulated them in vitro by TGF-ß, and profiled their transcriptomes using RNA-seq. Upon comparison, we identified a TGF-ß-induced signature of differentially expressed genes between TGF-ß-stimulated and -unstimulated cells. Next, we linked this in vitro TGF-ß-induced signature to a previously identified in vivo TRM-specific gene set and found considerable (>50%) overlap between the two gene sets, thus showing that a substantial part of the TRM signature can be attributed to TGF-ß signalling. Finally, gene set enrichment analysis further revealed that the altered gene signature following TGF-ß exposure reflected transcriptional signatures found in TRM cells from both epithelial and non-epithelial tissues. In summary, these findings show that TGF-ß has a broad footprint in establishing the residency-specific transcriptional profile of TRM cells, which is detectable in TRM cells from diverse tissues. They further suggest that constitutive TGF-ß signaling might be involved for their long-term persistence at tissue sites.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Transcriptoma , Fator de Crescimento Transformador beta/imunologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Memória Imunológica , Camundongos Endogâmicos C57BL
12.
Immunity ; 45(4): 889-902, 2016 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-27692609

RESUMO

In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Fígado/imunologia , Malária/imunologia , Animais , Linfócitos T CD8-Positivos/parasitologia , Culicidae , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Hepatócitos/imunologia , Hepatócitos/parasitologia , Fígado/parasitologia , Hepatopatias/imunologia , Hepatopatias/parasitologia , Vacinas Antimaláricas/imunologia , Camundongos , Plasmodium berghei/imunologia , Esporozoítos/imunologia , Esporozoítos/parasitologia , Vacinação/métodos
13.
PLoS Pathog ; 12(8): e1005799, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27540722

RESUMO

Disruption of T cell memory during severe immune suppression results in reactivation of chronic viral infections, such as Epstein Barr virus (EBV) and Cytomegalovirus (CMV). How different subsets of memory T cells contribute to the protective immunity against these viruses remains poorly defined. In this study we examined the compartmentalization of virus-specific, tissue resident memory CD8+ T cells in human lymphoid organs. This revealed two distinct populations of memory CD8+ T cells, that were CD69+CD103+ and CD69+CD103-, and were retained within the spleen and tonsils in the absence of recent T cell stimulation. These two types of memory cells were distinct not only in their phenotype and transcriptional profile, but also in their anatomical localization within tonsils and spleen. The EBV-specific, but not CMV-specific, CD8+ memory T cells preferentially accumulated in the tonsils and acquired a phenotype that ensured their retention at the epithelial sites where EBV replicates. In vitro studies revealed that the cytokine IL-15 can potentiate the retention of circulating effector memory CD8+ T cells by down-regulating the expression of sphingosine-1-phosphate receptor, required for T cell exit from tissues, and its transcriptional activator, Kruppel-like factor 2 (KLF2). Within the tonsils the expression of IL-15 was detected in regions where CD8+ T cells localized, further supporting a role for this cytokine in T cell retention. Together this study provides evidence for the compartmentalization of distinct types of resident memory T cells that could contribute to the long-term protection against persisting viral infections.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Herpesvirus Humano 4/imunologia , Memória Imunológica , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/patologia , Infecções por Citomegalovirus/patologia , Infecções por Vírus Epstein-Barr/patologia , Feminino , Humanos , Interleucina-15/imunologia , Fatores de Transcrição Kruppel-Like/imunologia , Masculino , Especificidade de Órgãos/imunologia
14.
Science ; 352(6284): 459-63, 2016 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-27102484

RESUMO

Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.


Assuntos
Regulação da Expressão Gênica , Genes Reguladores/fisiologia , Memória Imunológica/genética , Células Matadoras Naturais/imunologia , Células T Matadoras Naturais/imunologia , Fatores de Transcrição/fisiologia , Animais , Trato Gastrointestinal/imunologia , Genes Reguladores/genética , Rim/imunologia , Fígado/imunologia , Ativação Linfocitária , Camundongos , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo , Pele/imunologia , Fatores de Transcrição/genética , Transcrição Gênica , Regulação para Cima
15.
Immunity ; 44(2): 233-45, 2016 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-26872694

RESUMO

According to in vitro assays, T cells are thought to kill rapidly and efficiently, but the efficacy and dynamics of cytotoxic T lymphocyte (CTL)-mediated killing of virus-infected cells in vivo remains elusive. We used two-photon microscopy to quantify CTL-mediated killing in mice infected with herpesviruses or poxviruses. On average, one CTL killed 2-16 virus-infected cells per day as determined by real-time imaging and by mathematical modeling. In contrast, upon virus-induced MHC class I downmodulation, CTLs failed to destroy their targets. During killing, CTLs remained migratory and formed motile kinapses rather than static synapses with targets. Viruses encoding the calcium sensor GCaMP6s revealed strong heterogeneity in individual CTL functional capacity. Furthermore, the probability of death of infected cells increased for those contacted by more than two CTLs, indicative of CTL cooperation. Thus, direct visualization of CTLs during killing of virus-infected cells reveals crucial parameters of CD8(+) T cell immunity.


Assuntos
Infecções por Herpesviridae/imunologia , Muromegalovirus/imunologia , Perforina/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Vaccinia virus/imunologia , Vacínia/imunologia , Animais , Sinalização do Cálcio , Comunicação Celular , Células Cultivadas , Citotoxicidade Imunológica , Humanos , Evasão da Resposta Imune , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microscopia de Fluorescência por Excitação Multifotônica , Perforina/genética , Subpopulações de Linfócitos T/virologia , Linfócitos T Citotóxicos/virologia
16.
Science ; 351(6269): 186-90, 2016 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-26657283

RESUMO

The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis.


Assuntos
Quimiocina CCL21/metabolismo , Quimiotaxia , Células Dendríticas/fisiologia , Linfonodos/fisiologia , Processamento de Proteína Pós-Traducional , Receptores CCR7/metabolismo , Ácidos Siálicos/metabolismo , Animais , Células da Medula Óssea/fisiologia , Glicosilação , Ligantes , Linfonodos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes
17.
Immunity ; 43(6): 1101-11, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26682984

RESUMO

Tissue-resident memory T (Trm) cells contribute to local immune protection in non-lymphoid tissues such as skin and mucosa, but little is known about their transcriptional regulation. Here we showed that CD8(+)CD103(+) Trm cells, independent of circulating memory T cells, were sufficient for protection against infection and described molecular elements that were crucial for their development in skin and lung. We demonstrated that the T-box transcription factors (TFs) Eomes and T-bet combined to control CD8(+)CD103(+) Trm cell formation, such that their coordinate downregulation was crucial for TGF-ß cytokine signaling. TGF-ß signaling, in turn, resulted in reciprocal T-box TF downregulation. However, whereas extinguishment of Eomes was necessary for CD8(+)CD103(+) Trm cell development, residual T-bet expression maintained cell surface interleukin-15 (IL-15) receptor ß-chain (CD122) expression and thus IL-15 responsiveness. These findings indicate that the T-box TFs control the two cytokines, TGF-ß and IL-15, which are pivotal for CD8(+)CD103(+) Trm cell development and survival.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Interleucina-15/imunologia , Proteínas com Domínio T/imunologia , Fator de Crescimento Transformador beta/imunologia , Transferência Adotiva , Animais , Regulação para Baixo , Citometria de Fluxo , Regulação da Expressão Gênica/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Knockout , Reação em Cadeia da Polimerase , Subpopulações de Linfócitos T/imunologia
18.
J Immunol ; 194(5): 2059-63, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25624457

RESUMO

Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor S1P1. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/imunologia , Antígenos Virais/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Lectinas Tipo C/imunologia , Receptores de Lisoesfingolipídeo/imunologia , Imunidade Adaptativa , Animais , Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos Virais/genética , Linfócitos T CD8-Positivos/patologia , Linfócitos T CD8-Positivos/virologia , Técnicas de Cocultura , Células Dendríticas/imunologia , Células Dendríticas/patologia , Células Dendríticas/virologia , Feminino , Regulação da Expressão Gênica , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/imunologia , Imunofenotipagem , Interferon Tipo I/genética , Interferon Tipo I/imunologia , Lectinas Tipo C/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Lisoesfingolipídeo/genética , Transdução de Sinais , Pele/imunologia , Pele/patologia , Pele/virologia
19.
Nat Immunol ; 15(7): 623-30, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24813163

RESUMO

Afferent lymph-borne dendritic cells essentially rely on the chemokine receptor CCR7 for their transition from the subcapsular lymph node sinus into the parenchyma, a migratory step driven by putative gradients of CCR7 ligands. We found that lymph node fringes indeed contained physiological gradients of the chemokine CCL21, which depended on the expression of CCRL1, the atypical receptor for the CCR7 ligands CCL19 and CCL21. Lymphatic endothelial cells lining the ceiling of the subcapsular sinus, but not those lining the floor, expressed CCRL1, which scavenged chemokines from the sinus lumen. This created chemokine gradients across the sinus floor and enabled the emigration of dendritic cells. In vitro live imaging revealed that spatially confined expression of CCRL1 was necessary and sufficient for the creation of functional chemokine gradients.


Assuntos
Quimiocina CCL21/fisiologia , Linfonodos/imunologia , Receptores CCR/fisiologia , Animais , Movimento Celular , Células Dendríticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL
20.
Proc Natl Acad Sci U S A ; 111(14): 5307-12, 2014 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-24706879

RESUMO

Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (TRM). In the skin, these memory CD8(+) T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal TRM preferentially at the site of prior infection despite sustained migration. Computational simulation of TRM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of TRM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin TRM. Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche.


Assuntos
Memória Imunológica , Pele/imunologia , Linfócitos T/imunologia , Transferência Adotiva , Animais , Movimento Celular , Citometria de Fluxo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia/métodos
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