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1.
JCI Insight ; 3(5)2018 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-29515032

RESUMO

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic stem cell transplantation induced by the influx of donor-derived effector T cells (TE) into peripheral tissues. Current treatment strategies rely on targeting systemic T cells; however, the precise location and nature of instructions that program TE to become pathogenic and trigger injury are unknown. We therefore used weighted gene coexpression network analysis to construct an unbiased spatial map of TE differentiation during the evolution of GVHD and identified wide variation in effector programs in mice and humans according to location. Idiosyncrasy of effector programming in affected organs did not result from variation in T cell receptor repertoire or the selection of optimally activated TE. Instead, TE were reprogrammed by tissue-autonomous mechanisms in target organs for site-specific proinflammatory functions that were highly divergent from those primed in lymph nodes. In the skin, we combined the correlation-based network with a module-based differential expression analysis and showed that Langerhans cells provided in situ instructions for a Notch-dependent T cell gene cluster critical for triggering local injury. Thus, the principal determinant of TE pathogenicity in GVHD is the final destination, highlighting the need for target organ-specific approaches to block immunopathology while avoiding global immune suppression.


Assuntos
Reprogramação Celular/imunologia , Doença Enxerto-Hospedeiro/imunologia , Células de Langerhans/imunologia , Pele/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Superfície/genética , Antígenos de Superfície/metabolismo , Transplante de Medula Óssea/efeitos adversos , Células Cultivadas , Reprogramação Celular/genética , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/imunologia , Doença Enxerto-Hospedeiro/patologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Células de Langerhans/metabolismo , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Masculino , Lectinas de Ligação a Manose/genética , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Família Multigênica/genética , Família Multigênica/imunologia , Cultura Primária de Células , Receptores Notch/metabolismo , Pele/citologia , Pele/patologia , Linfócitos T Citotóxicos/metabolismo , Quimeras de Transplante , Transplante Homólogo/efeitos adversos
2.
Eur J Immunol ; 46(1): 192-203, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26464217

RESUMO

Dendritic cells (DCs) play a vital role in innate and adaptive immunities. Inducible depletion of CD11c(+) DCs engineered to express a high-affinity diphtheria toxin receptor has been a powerful tool to dissect DC function in vivo. However, despite reports showing that loss of DCs induces transient monocytosis, the monocyte population that emerges and the potential impact of monocytes on studies of DC function have not been investigated. We found that depletion of CD11c(+) cells from CD11c.DTR mice induced the expansion of a variant CD64(+) Ly6C(+) monocyte population in the spleen and blood that was distinct from conventional monocytes. Expansion of CD64(+) Ly6C(+) monocytes was independent of mobilization from the BM via CCR2 but required the cytokine, G-CSF. Indeed, this population was also expanded upon exposure to exogenous G-CSF in the absence of DC depletion. CD64(+) Ly6C(+) monocytes were characterized by upregulation of innate signaling apparatus despite the absence of inflammation, and an increased capacity to produce TNF-α following LPS stimulation. Thus, depletion of CD11c(+) cells induces expansion of a unique CD64(+) Ly6C(+) monocyte population poised to synthesize TNF-α. This finding will require consideration in experiments using depletion strategies to test the role of CD11c(+) DCs in immunity.


Assuntos
Células Dendríticas/imunologia , Monócitos/citologia , Monócitos/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Animais , Antígenos Ly/imunologia , Antígeno CD11c/imunologia , Citometria de Fluxo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Análise de Sequência com Séries de Oligonucleotídeos , Receptores de IgG/imunologia , Fator de Necrose Tumoral alfa/imunologia
3.
Blood ; 117(26): 7063-9, 2011 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-21566096

RESUMO

Langerhans cells (LCs) are a distinct population of dendritic cells that form a contiguous network in the epidermis of the skin. Although LCs possess many of the properties of highly proficient dendritic cells, recent studies have indicated that they are not necessary to initiate cutaneous immunity. In this study, we used a tractable model of cutaneous GVHD, induced by topical application of a Toll-like receptor agonist, to explore the role of LCs in the development of tissue injury. By adapting this model to permit inducible and selective depletion of host LCs, we found that GVHD was significantly reduced when LCs were absent. However, LCs were not required either for CD8 T-cell activation within the draining lymph node or subsequent homing of effector cells to the epidermis. Instead, we found that LCs were necessary for inducing transcription of IFN-γ and other key effector molecules by donor CD8 cells in the epidermis, indicating that they license CD8 cells to induce epithelial injury. These data demonstrate a novel regulatory role for epidermal LCs during the effector phase of an inflammatory immune response in the skin.


Assuntos
Comunicação Celular , Citotoxicidade Imunológica , Epiderme/imunologia , Epiderme/patologia , Células de Langerhans/imunologia , Linfócitos T Citotóxicos/imunologia , Aminoquinolinas/toxicidade , Animais , Células Cultivadas , Quimera , Epiderme/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Doença Enxerto-Hospedeiro/imunologia , Granzimas/genética , Granzimas/metabolismo , Imiquimode , Interferon gama/genética , Interferon gama/metabolismo , Células de Langerhans/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , RNA Mensageiro/metabolismo , Linfócitos T Citotóxicos/metabolismo , Ligante Indutor de Apoptose Relacionado a TNF/genética , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Receptores Toll-Like/agonistas , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
4.
J Immunol ; 186(8): 4565-72, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21389256

RESUMO

Cutaneous vaccination with lentiviral vectors generates systemic CD8 T cell responses that have the potential to eradicate tumors for cancer immunotherapy. However, although s.c. immunization with <1 million lentiviral particles clearly primes cytotoxic T cells, vaccination with much higher doses has routinely been used to define the mechanisms of T cell activation by lentiviral vectors. In particular, experiments to test presentation of lentiviral Ags by dendritic cells (DC) require injection of high viral titers, which may result in aberrant transduction of different DC populations. We exploited inducible murine models of DC depletion to investigate which DC prime the lentiviral response after s.c. immunization with low doses of lentiviral particles. In this article, we demonstrate that conventional DC are required to present Ag to CD8 T cells in draining lymph nodes. Langerhans cells are not required to activate the effector response, and neither Langerhans cells nor plasmacytoid DC are sufficient to prime Ag-specific T cells. Immunization drives the generation of endogenous long-lived memory T cells that can be reactivated to kill Ag-specific targets in the absence of inflammatory challenge. Furthermore, lentiviral vaccination activates expansion of endogenous CD4 Th cells, which are required for the generation of effector CD8 T cells that produce IFN-γ and kill Ag-specific targets. Collectively, we demonstrate that after cutaneous immunization with lentiviral particles, CD4-licensed lymph node conventional DC present Ag to CD8 T cells, resulting in the generation of protective endogenous antitumor immunity that may be effective for cancer immunotherapy.


Assuntos
Antígenos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos/genética , Antígenos/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Citocinas/imunologia , Citocinas/metabolismo , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Toxina Diftérica/toxicidade , Feminino , Citometria de Fluxo , Vetores Genéticos/genética , Células HEK293 , Humanos , Imunidade Celular/imunologia , Memória Imunológica/imunologia , Lentivirus/genética , Lentivirus/imunologia , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Linfócitos T Auxiliares-Indutores/metabolismo , Vacinação/métodos
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