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1.
Blood ; 117(4): 1196-204, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21051556

RESUMO

Increasing evidence suggests that neutrophils may participate in the regulation of adaptive immune responses, and can reach draining lymph nodes and cross-prime naive T cells. The aim of this study was to identify the mechanism(s) involved in the migration of neutrophils to the draining lymph nodes. We demonstrate that a subpopulation of human and mouse neutrophils express CCR7. CCR7 is rapidly expressed at the membrane upon stimulation. In vitro, stimulated human neutrophils migrate in response to the CCR7 ligands CCL19 and CCL21. In vivo, injection of complete Freund adjuvant induces a rapid recruitment of neutrophils to the lymph nodes in wild-type mice but not in Ccr7(-/-) mice. Moreover, intradermally injected interleukin-17-and granulocyte-macrophage colony-stimulating factor-stimulated neutrophils from wild-type mice, but not from Ccr7(-/-) mice, migrate to the draining lymph nodes. These results identify CCR7 as a chemokine receptor involved in the migration of neutrophils to the lymph nodes.


Assuntos
Movimento Celular/genética , Quimiotaxia de Leucócito/genética , Linfonodos/citologia , Neutrófilos/fisiologia , Receptores CCR7/fisiologia , Animais , Movimento Celular/imunologia , Células Cultivadas , Humanos , Linfonodos/imunologia , Linfonodos/metabolismo , Linfonodos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/genética , Neutrófilos/imunologia , Neutrófilos/metabolismo , Receptores CCR7/genética , Receptores CCR7/metabolismo
2.
J Immunol ; 186(7): 4175-82, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21368235

RESUMO

The nervous system influences immune responses through the release of neural factors such as neuropeptides. Among them, the tachykinin substance P (SP) signals via the neurokinin 1 receptor (NK-1R), which is expressed by various immune cells. We thereby analyzed in this paper whether tachykinins may participate in human CD4(+) Th cell polarization. We report that SP and hemokinin-1 (HK-1) upregulate IL-17A and IFN-γ production by human memory CD4(+) T cells without affecting IL-4 and IL-10 production. SP and HK-1 switch non-Th17-committed CD4(+) memory T cells into bona fide Th17 cells and Th1/Th17 cells. In contrast, SP and HK-1 do not modulate the polarization of naive CD4(+) T cells. SP- and HK-1-induced Th17 cell generation is mediated through NK-1R and requires the presence of monocytes. SP and HK-1 trigger IL-1ß, IL-6, and TNF-α production, upregulate IL-23 production, and enhance TNF-like 1A expression on monocyte surface. Neutralization experiments demonstrated that IL-1ß, IL-23, and TNF-like 1A are involved in the SP- and HK-1-induced Th17 cell. The other members of the tachykinin family, neurokinins A and B, have no effect on the differentiation of naive and memory T cells. These results thereby show that SP and HK-1 are novel Th17 cell-inducing factors that may act locally on memory T cells to amplify inflammatory responses.


Assuntos
Diferenciação Celular/imunologia , Memória Imunológica , Interleucina-1beta/biossíntese , Interleucina-23/biossíntese , Monócitos/imunologia , Substância P/fisiologia , Taquicininas/fisiologia , Células Th17/imunologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/biossíntese , Comunicação Celular/genética , Comunicação Celular/imunologia , Diferenciação Celular/genética , Polaridade Celular/genética , Polaridade Celular/imunologia , Células Cultivadas , Humanos , Memória Imunológica/genética , Mediadores da Inflamação/fisiologia , Interleucina-1beta/genética , Interleucina-1beta/fisiologia , Interleucina-23/genética , Interleucina-23/fisiologia , Monócitos/metabolismo , Monócitos/patologia , Células Th17/metabolismo , Células Th17/patologia , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 15 da Superfamília de Ligantes de Fatores de Necrose Tumoral/fisiologia
3.
J Hepatol ; 52(5): 644-51, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20338659

RESUMO

BACKGROUNDS & AIMS: The hepatitis C virus NS3 protein is taken up by myeloid cells in a TLR2-independent manner and activates myeloid cells via TLR2. This study aimed to identify the endocytic receptor(s) involved in the uptake of NS3 by myeloid cells and its relation with TLR2. METHODS: Inhibitors and transfected cells were used to identify the nature of the NS3-binding receptors expressed by myeloid cells. The cooperation between scavenger receptors (SRs) and TLR2 in the NS3-mediated activation of myeloid cells was evaluated using inhibitors, cells from TLR2(-/-) mice, and confocal microscopy. The involvement of SRs in NS3 cross-presentation was evaluated in vitro using an NS3-specific human T-cell clone. RESULTS: We observed that SRs are the main binding structures for NS3 on myeloid cells and identified the SRs SRA-1 and SREC-I as endocytic receptors for NS3. Moreover, both SRs and TLR2 cooperate in NS3-induced myeloid cell activation. CONCLUSION: This study highlights a central role for SRs in NS3 uptake and cross-presentation, and demonstrates a tightly orchestrated cooperation between signalling and endocytic innate receptors in NS3 recognition.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Células Dendríticas/imunologia , Hepacivirus/imunologia , Receptores Depuradores/imunologia , Receptores Depuradores Classe F/fisiologia , Receptor 2 Toll-Like/fisiologia , Proteínas não Estruturais Virais/imunologia , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células CHO , Diferenciação Celular , Cricetinae , Cricetulus , Células Dendríticas/citologia , Células Dendríticas/virologia , Endocitose , Humanos , Receptores de Lipopolissacarídeos/imunologia , Camundongos , Monócitos/citologia , Monócitos/fisiologia , Células Mieloides/fisiologia , Receptores Depuradores/metabolismo , Proteínas Recombinantes/imunologia , Transfecção , Proteínas não Estruturais Virais/genética , Proteínas não Estruturais Virais/metabolismo
4.
Eur J Immunol ; 39(10): 2877-84, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19728309

RESUMO

NK lymphocytes and type I IFN (IFN-alpha/beta) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-beta (but not IFN-alpha) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-beta Ab prevented the production of IFN-gamma induced by polyI:C plus IL-2/IL-12. Similarly, IFN-gamma production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1(-/-) compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-gamma production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-beta that induce, in an autocrine manner, the production of IFN-gamma and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.


Assuntos
Comunicação Autócrina/imunologia , Interferon beta/metabolismo , Interferon gama/metabolismo , Interleucina-12/farmacologia , Interleucina-2/farmacologia , Células Matadoras Naturais/metabolismo , Poli I-C/farmacologia , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Linhagem Celular , Células Cultivadas , RNA Helicases DEAD-box/genética , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Humanos , Helicase IFIH1 Induzida por Interferon , Interferon beta/genética , Interferon beta/imunologia , Interferon beta/farmacologia , Interferon gama/genética , Células Matadoras Naturais/efeitos dos fármacos , Cinética , Camundongos , Camundongos Endogâmicos , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/imunologia , Receptores de Interleucina-12/genética , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT4/metabolismo , Receptor 3 Toll-Like/genética
5.
Glia ; 56(1): 69-77, 2008 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-17932942

RESUMO

Some observations have suggested that cells from the central nervous system (CNS) could present exogenous antigens on major histocompatibility complex (MHC) class I molecules to CD8(+) T cells (a process called cross-presentation). Microglia are the major myeloid immunocompetent cells of the CNS. When activated, following the injury of the nervous parenchyma, they become fully competent antigen-presenting cells (APC) that prime CD4(+) T lymphocytes. We therefore tested the cross-presentation capacity of murine microglia. We report that a microglial cell line (C8-B4), neonatal microglia, and interestingly adult microglia cross-present soluble exogenous antigen (ovalbumin) to a OVA-specific CD8(+) T-cell hybridoma and cross-prime OVA-specific naive OT-1 CD8(+) T cells. In both these cases, C8-B4 and neonatal microglia cross-present OVA as well as peritoneal macrophages. Although cross-presentation by adult microglia is less efficient, it is increased by GM-CSF and CpG oligodeoxynucleotide (ODN) stimulation. Using microglial cells either exposed to an inhibitor of proteasome, lactacystin, or purified from TAP(-/-) mice, we demonstrate that the microglia cross-present antigen in proteasome- and TAP-dependant pathways, respectively. Last, microglia purified from adult mice injected intracerebrally with OVA efficiently stimulate OVA-specific CD8(+) T cells, thereby showing that microglia take up and process exogenous antigen into MHC class I in vivo. This first demonstration of the cross-presentation property of microglia offers novel therapeutic approaches to modulate CD8 T-cell responses in the brain.


Assuntos
Envelhecimento/imunologia , Animais Recém-Nascidos/imunologia , Células Apresentadoras de Antígenos/imunologia , Antígenos/imunologia , Microglia/imunologia , Animais , Antígenos CD8/imunologia , Linhagem Celular , Células Cultivadas , Citometria de Fluxo , Genes MHC Classe I/genética , Genes MHC Classe I/imunologia , Inflamação/imunologia , Inflamação/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Ovalbumina/imunologia , Fenótipo , Complexo de Endopeptidases do Proteassoma , Linfócitos T/imunologia
6.
Blood ; 110(8): 2965-73, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17562875

RESUMO

Neutrophils are professional phagocytes that migrate early, in high number, to the infection sites. Our study has analyzed how neutrophils cross-present antigens and influence CD8+ T-cell responses. By using highly purified neutrophils from peritoneal exudates and bone marrow, we have shown that neutrophils cross-present ovalbumin to a CD8+ T-cell hybridoma and to naive CD8+ T cells from OT1 transgenic mice. Cross-presentation by neutrophils was TAP and proteasome dependent and was as efficient as in macrophages. Moreover, it actually occurred earlier than in professional antigen-presenting cells. Peritoneal exudate neutrophils from mice injected intraperitoneally with ovalbumin also cross-presented ovalbumin, proving that neutrophils take up and present exogenous antigens into major histocompatibility complex I (MHC I) molecules in vivo. We then evaluated the in vivo influence of antigen cross-presentation by neutrophils on CD8+ T-cell response using beta2-microglobulin-deficient mice transferred with OT1 CD8+ T cells and injected with ovalbumin-pulsed neutrophils. Four days after neutrophil injection, OT1 cells proliferated and expressed effector functions (IFN-gamma production and cytolysis). They also responded efficiently to a rechallenge with ovalbumin-pulsed dendritic cells in CFA. These data are the first demonstration that neutrophils cross-prime CD8+ T cells in vivo and suggest that they may constitute, together with professional antigen-presenting cells, an attractive target to induce cytotoxic T cells in vaccines.


Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Apresentação Cruzada/imunologia , Ativação Linfocitária/imunologia , Neutrófilos/imunologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Líquido Ascítico/citologia , Células da Medula Óssea/imunologia , Linfócitos T CD8-Positivos/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Neutrófilos/metabolismo , Ovalbumina/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo
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