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1.
J Immunol ; 205(7): 1842-1856, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32839238

RESUMO

Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/metabolismo , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Animais , Apresentação do Antígeno , Autoantígenos/imunologia , Autoantígenos/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Imunidade Humoral , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/genética , Vacinação
2.
Nature ; 566(7745): E10, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30742076

RESUMO

Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were…'. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.

3.
Nature ; 565(7739): 366-371, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30598548

RESUMO

The immune system can suppress tumour development both by eliminating malignant cells and by preventing the outgrowth and spread of cancer cells that resist eradication1. Clinical and experimental data suggest that the latter mode of control-termed cancer-immune equilibrium1-can be maintained for prolonged periods of time, possibly up to several decades2-4. Although cancers most frequently originate in epithelial layers, the nature and spatiotemporal dynamics of immune responses that maintain cancer-immune equilibrium in these tissue compartments remain unclear. Here, using a mouse model of transplantable cutaneous melanoma5, we show that tissue-resident memory CD8+ T cells (TRM cells) promote a durable melanoma-immune equilibrium that is confined to the epidermal layer of the skin. A proportion of mice (~40%) transplanted with melanoma cells remained free of macroscopic skin lesions long after epicutaneous inoculation, and generation of tumour-specific epidermal CD69+ CD103+ TRM cells correlated with this spontaneous disease control. By contrast, mice deficient in TRM formation were more susceptible to tumour development. Despite being tumour-free at the macroscopic level, mice frequently harboured melanoma cells in the epidermal layer of the skin long after inoculation, and intravital imaging revealed that these cells were dynamically surveyed by TRM cells. Consistent with their role in melanoma surveillance, tumour-specific TRM cells that were generated before melanoma inoculation conferred profound protection from tumour development independently of recirculating T cells. Finally, depletion of TRM cells triggered tumour outgrowth in a proportion (~20%) of mice with occult melanomas, demonstrating that TRM cells can actively suppress cancer progression. Our results show that TRM cells have a fundamental role in the surveillance of subclinical melanomas in the skin by maintaining cancer-immune equilibrium. As such, they provide strong impetus for exploring these cells as targets of future anticancer immunotherapies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Pele/imunologia , Idoso , Animais , Progressão da Doença , Epiderme/imunologia , Epiderme/patologia , Feminino , Humanos , Masculino , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Transplante de Neoplasias , Pele/patologia , Neoplasias Cutâneas/patologia
4.
Nat Immunol ; 19(2): 183-191, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29311695

RESUMO

Although tissue-resident memory T cells (TRM cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin TRM cells engaged virus-infected cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary TRM cells formed from pre-existing TRM cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander TRM cells were generated in the skin without displacement of the pre-existing TRM cell pool. Thus, pre-existing skin TRM cell populations are not displaced after subsequent infections, which enables multiple TRM cell specificities to be stably maintained within the tissue.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Memória Imunológica/imunologia , Pele/imunologia , Animais , Proliferação de Células/fisiologia , Herpes Simples/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos
5.
J Immunol ; 199(7): 2451-2459, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28855310

RESUMO

Infection or inflammation of the skin recruits effector CD8+ T cells that enter the epidermis and form populations of long-lived tissue-resident memory T (TRM) cells. These skin TRM cells migrate within the constrained epidermal environment by extending multiple dynamic dendritic projections and squeezing between keratinocytes to survey the tissue for pathogens. In this study, we examined the signals required for this distinctive mode of T cell migration by inhibiting key cytoskeletal components and performing intravital two-photon microscopy to visualize TRM cell behavior. We found that TRM cell motility and dendrite formation required an intact actomyosin cytoskeleton and the Rho-associated coiled-coil containing kinases. We also identified an essential role for microtubules for maintaining skin TRM cell shape and cellular integrity. We reveal a role for pertussis toxin-sensitive signaling for TRM cell dendritic morphology and migration that is independent of CXCR3 or CXCR6, or the skin-selective chemokine receptors CCR10 and CCR8. However, we found that CXCR6 and CCR10 expression by CD8+ T cells was required for the optimal formation of memory T cell populations, in particular TRM cell populations in the skin.


Assuntos
Linfócitos T CD8-Positivos/fisiologia , Movimento Celular , Epiderme/imunologia , Memória Imunológica , Receptores de Quimiocinas/metabolismo , Pele/imunologia , Actomiosina/metabolismo , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/fisiologia , Células Epidérmicas , Microscopia Intravital/métodos , Camundongos , Microtúbulos/metabolismo , Toxina Pertussis/metabolismo , Receptores CCR10/genética , Receptores CCR10/metabolismo , Receptores CCR8/metabolismo , Receptores CXCR/genética , Receptores CXCR/metabolismo , Receptores CXCR3/metabolismo , Receptores CXCR6 , Receptores de Quimiocinas/genética , Transdução de Sinais , Pele/anatomia & histologia , Pele/citologia , Quinases Associadas a rho/metabolismo
6.
Cell Rep ; 18(2): 406-418, 2017 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-28076785

RESUMO

Lymph nodes (LNs) are constructed of intricate networks of endothelial and mesenchymal stromal cells. How these lymphoid stromal cells (LSCs) regulate lymphoid tissue remodeling and contribute to immune responses remains poorly understood. We performed a comprehensive functional and transcriptional analysis of LSC responses to skin viral infection and found that LSC subsets responded robustly, with different kinetics for distinct pathogens. Recruitment of cells to inflamed LNs induced LSC expansion, while B cells sustained stromal responses in an antigen-independent manner. Infection induced rapid transcriptional responses in LSCs. This transcriptional program was transient, returning to homeostasis within 1 month of infection, yet expanded fibroblastic reticular cell networks persisted for more than 3 months after infection, and this altered LN composition reduced the magnitude of LSC responses to subsequent heterologous infection. Our results reveal the complexity of LSC responses during infection and suggest that amplified networks of LN stromal cells support successive immune responses.


Assuntos
Linfonodos/patologia , Viroses/imunologia , Viroses/patologia , Animais , Antígenos Virais/imunologia , Linfócitos B/imunologia , Proliferação de Células , Coinfecção/imunologia , Regulação da Expressão Gênica , Cinética , Camundongos Endogâmicos C57BL , Células Estromais/patologia , Transcrição Genética , Viroses/genética
7.
Sci Rep ; 7: 41091, 2017 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-28112242

RESUMO

Neutrophils rapidly infiltrate sites of inflammation during peripheral infection or tissue injury. In addition to their well described roles as pro-inflammatory phagocytes responsible for pathogen clearance, recent studies have demonstrated a broader functional repertoire including mediating crosstalk between innate and adaptive arms of the immune system. Specifically, neutrophils have been proposed to mediate antigen transport to lymph nodes (LN) to modulate T cell priming and to influence T cell migration to infected tissues. Using a mouse model of cutaneous herpes simplex virus type 1 (HSV-1) infection we explored potential contributions of neutrophils toward anti-viral immunity. While a transient, early influx of neutrophils was triggered by dermal scarification, we did not detect migration of neutrophils from the skin to LN. Furthermore, despite recruitment of neutrophils into LN from the blood, priming and expansion of CD4+ and CD8+ T cells was unaffected following neutrophil depletion. Finally, we found that neutrophils were dispensable for the migration of effector T cells into infected skin. Our study suggests that the immunomodulatory roles of neutrophils toward adaptive immunity may be context-dependent, and are likely determined by the type of pathogen and anatomical site of infection.


Assuntos
Herpes Simples/imunologia , Herpesvirus Humano 1/patogenicidade , Inflamação/imunologia , Linfócitos T/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Herpes Simples/patologia , Herpes Simples/virologia , Herpesvirus Humano 1/imunologia , Humanos , Imunomodulação/imunologia , Inflamação/patologia , Inflamação/virologia , Camundongos , Camundongos Endogâmicos C57BL , Neutrófilos/imunologia , Pele/imunologia , Pele/virologia
8.
Immunity ; 43(3): 554-65, 2015 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-26297566

RESUMO

The dynamics of when and where CD4(+) T cells provide help for CD8(+) T cell priming and which dendritic cells (DCs) activate CD4(+) T cells in vivo after localized infection are poorly understood. By using a cutaneous herpes simplex virus infection model combined with intravital 2-photon imaging of the draining lymph node (LN) to concurrently visualize pathogen-specific CD4(+) and CD8(+) T cells, we found that early priming of CD4(+) T cells involved clustering with migratory skin DCs. CD8(+) T cells did not interact with migratory DCs and their activation was delayed, requiring later clustering interactions with LN-resident XCR1(+) DCs. CD4(+) T cells interacted with these late CD8(+) T cell clusters on resident XCR1(+) DCs. Together, these data reveal asynchronous T cell activation by distinct DC subsets and highlight the key role of XCR1(+) DCs as the central platform for cytotoxic T lymphocyte activation and the delivery of CD4(+) T cell help.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Linfonodos/imunologia , Animais , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Movimento Celular/imunologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Corantes Fluorescentes/química , Herpes Simples/imunologia , Herpes Simples/metabolismo , Herpes Simples/virologia , Interações Hospedeiro-Patógeno/imunologia , Linfonodos/citologia , Linfonodos/virologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência por Excitação Multifotônica , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Rodaminas/química , Simplexvirus/imunologia , Simplexvirus/fisiologia
9.
J Exp Med ; 211(13): 2549-66, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25422492

RESUMO

DOCK8 mutations result in an inherited combined immunodeficiency characterized by increased susceptibility to skin and other infections. We show that when DOCK8-deficient T and NK cells migrate through confined spaces, they develop cell shape and nuclear deformation abnormalities that do not impair chemotaxis but contribute to a distinct form of catastrophic cell death we term cytothripsis. Such defects arise during lymphocyte migration in collagen-dense tissues when DOCK8, through CDC42 and p21-activated kinase (PAK), is unavailable to coordinate cytoskeletal structures. Cytothripsis of DOCK8-deficient cells prevents the generation of long-lived skin-resident memory CD8 T cells, which in turn impairs control of herpesvirus skin infections. Our results establish that DOCK8-regulated shape integrity of lymphocytes prevents cytothripsis and promotes antiviral immunity in the skin.


Assuntos
Forma Celular/imunologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Imunidade , Células Matadoras Naturais/patologia , Pele/imunologia , Pele/virologia , Linfócitos T/patologia , Animais , Apoptose/efeitos dos fármacos , Bovinos , Adesão Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/patologia , Forma Celular/efeitos dos fármacos , Quimiocina CXCL12/farmacologia , Quimiotaxia/efeitos dos fármacos , Colágeno/farmacologia , Citoesqueleto/efeitos dos fármacos , Citoesqueleto/metabolismo , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Humanos , Imunidade/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Proteína cdc42 de Ligação ao GTP/metabolismo , Quinases Ativadas por p21/metabolismo
10.
PLoS Pathog ; 10(8): e1004303, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25121482

RESUMO

Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ-producing CD4+ T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing CD8+ T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by CD4+ T cells, CD8+ T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN-γ production by CD8+ T-cells. Thus, we describe a previously unappreciated complexity in the regulation of CD4+ and CD8+ T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC).


Assuntos
Células Apresentadoras de Antígenos/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Herpes Simples/imunologia , Dermatopatias Infecciosas/imunologia , Transferência Adotiva , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Imunofluorescência , Herpesvirus Humano 1/imunologia , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal
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