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1.
Eur J Immunol ; 46(3): 609-18, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26626316

RESUMO

The elimination of solid tumors largely depends on effective T-cell priming by dendritic cells (DCs). For decades, studies focusing on antitumoral immune responses have been performed with tumors transplanted subcutaneously (s.c.). These studies however do not take into account the heterogeneous tissue distribution and functionality of the different DC subsets. Given the crucial role of DCs in inducing protective immune response, we postulated that the anatomic location of tumor development may greatly impact tumor immunogenicity. We therefore implanted tumor cells either in the DC-rich dermis environment or in the s.c. tissue that mainly contains macrophages and monocytes. We showed that intradermal (i.d.), but not s.c. tumors are rapidly rejected in a T-cell-dependent manner and induce protective T-cell responses. The rejection of i.d. tumors correlates with rapid recruitment of dermal DCs presenting the tumor antigen to both CD4 and CD8 T cells in the draining lymph nodes (dLNs). The same DC subsets were mobilized upon s.c. tumor transplantation but with delayed kinetics. Altogether, our results show that the anatomical site of tumor development influences tumor immunogenicity, notably by controlling the kinetics of DC mobilization in the draining LNs.


Assuntos
Células Dendríticas/imunologia , Linfonodos/citologia , Neoplasias/imunologia , Animais , Apresentação de Antígeno , Antígenos de Neoplasias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/fisiologia , Derme/imunologia , Células de Langerhans/imunologia , Ativação Linfocitária , Camundongos , Neoplasias/fisiopatologia , Tela Subcutânea/imunologia
2.
J Exp Med ; 208(1): 3-11, 2011 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-21173102

RESUMO

Thymus-specific serine protease (TSSP) is a novel protease that may contribute to the generation of the peptide repertoire presented by MHC class II molecules in the thymus. Although TSSP deficiency has no quantitative impact on the development of CD4 T cells expressing a polyclonal T cell receptor (TCR) repertoire, the development of CD4 T cells expressing the OTII and Marilyn transgenic TCRs is impaired in TSSP-deficient mice. In this study, we assess the role of TSSP in shaping the functional endogenous polyclonal CD4 T cell repertoire by analyzing the response of TSSP-deficient mice to several protein antigens (Ags). Although TSSP-deficient mice responded normally to most of the Ags tested, they responded poorly to hen egg lysozyme (HEL). The impaired CD4 T cell response of TSSP-deficient mice to HEL correlated with significant alteration of the dominant TCR-ß chain repertoire expressed by HEL-specific CD4 T cells, suggesting that TSSP is necessary for the intrathymic development of cells expressing these TCRs. Thus, TSSP contributes to the diversification of the functional endogenous CD4 T cell TCR repertoire in the thymus.


Assuntos
Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Serina Endopeptidases/metabolismo , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/citologia , Proliferação de Células , Camundongos , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T/química , Serina Endopeptidases/deficiência
3.
J Immunol ; 182(11): 6807-14, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19454676

RESUMO

NFAT transcription factors play critical roles in CD4 T cell activation and differentiation. Their function in CD8 T cell is, however, unknown. We show in this study that, in contrast to CD4 T cells, Ag-stimulated CD8 T cells do not demonstrate NFAT transcriptional activity despite normal regulation of NFAT nuclear shuttling. Further analysis of the signaling defect shows that phosphorylation of the (53)SSPS(56) motif of the NFAT transactivation domain is essential for NFAT-mediated transcription in primary T cells. Although Ag stimulation induces in CD4 T cells extensive phosphorylation of this motif, it does so only minimally in CD8 T cells. Although Ag stimulation triggers only modest activation of the p38 MAPK in CD8 T cells as opposed to CD4 T cells, p38 MAPK is not the upstream kinase that directly or indirectly phosphorylates the NFAT (53)SSPS(56) motif. These findings reveal an unsuspected difference between CD4 and CD8 T cells in the TCR downstream signaling pathway. Therefore, whereas in CD4 T cells TCR/CD28 engagement activates a yet unknown kinase that can phosphorylate the NFAT (53)SSPS(56) motif, this pathway is only minimally triggered in CD8 T cells, thus limiting NFAT transcriptional activity.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Ativação Linfocitária , Fatores de Transcrição NFATC/metabolismo , Ativação Transcricional , Transporte Ativo do Núcleo Celular , Motivos de Aminoácidos , Animais , Antígenos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Camundongos , Fosforilação
4.
Proc Natl Acad Sci U S A ; 105(7): 2550-5, 2008 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-18268354

RESUMO

The molecular mechanisms used by regulatory T cells (Treg) to inhibit the effector phase of adaptive immune responses are still elusive. In the present work, we investigated the possibility that Treg may interfere with a basic biological function of T helper cells (T(H)): polarization of secretory machinery for dedicated help delivery. To address this question, we visualized by confocal microscopy different parameters of activation in T(H) and Treg cells interacting simultaneously with individual antigen-presenting cells (APC). Our results show that, although productive TCR engagement in T(H)/APC conjugates was unaffected by the presence of adjacent Treg, the reorientation of T(H) secretory machinery toward APC was strongly inhibited. Blocking TGF-beta completely reverted Treg induced inhibition of T(H) polarization. Our results identify a previously undescribed mechanism by which Treg inhibit effector T cells. TGF-beta produced by adjacent Treg interferes with polarization of T(H) secretory machinery toward APC, thus affecting a crucial step of T(H)-mediated amplification of the immune response.


Assuntos
Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Polaridade Celular/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/metabolismo , Cálcio/metabolismo , Separação Celular , Células Cultivadas , Humanos , Interferon gama/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/metabolismo , Fatores de Tempo
5.
Int Immunol ; 19(3): 239-48, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17220479

RESUMO

Upon conjugation with cognate antigen-presenting cells (APCs), T lymphocytes undergo a sustained [Ca(2+)](i) increase resulting from the engagement of TCR and of accessory molecules with ligands expressed on the surface of APCs. We investigated the contribution of the accessory molecule CD2 to the activation of phospholipase Cgamma1 (PLCgamma1)/calcium pathway in antigen-stimulated T cells. We show that CD2 binding with its ligand CD58 expressed on the surface of APCs augments and sustains antigen-induced [Ca(2+)](i) increase in individual T cells interacting with APCs. We also show that in conditions in which CD2-CD58 interaction is impeded, the recruitment of PLCgamma1 to the immunological synapse (IS) is reduced. Interestingly, in these conditions PLCgamma1 phosphorylation in the regulatory tyrosine 783 is also defective. Our results indicate that TCR- and CD2-derived signals converge for the recruitment and activation of PLCgamma1 at the IS and shed new light on the accessory function of CD2 in T cell activation by specific antigen.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Antígenos CD2/metabolismo , Sinalização do Cálcio , Comunicação Celular/imunologia , Fosfolipase C gama/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/enzimologia , Proteína-Tirosina Quinase ZAP-70/metabolismo , Células Apresentadoras de Antígenos/imunologia , Antígenos CD58/metabolismo , Linhagem Celular , Ativação Enzimática , Humanos , Ativação Linfocitária , Microscopia Confocal , Fosforilação , Transporte Proteico , Linfócitos T/imunologia
6.
Immunol Lett ; 98(1): 57-61, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15790509

RESUMO

The immunological synapse (IS) is a specialized signaling area formed at the contact site between T-cells and antigen-presenting cells (APC), where sustained engagement and signaling of TCR and accessory molecules occur. A key feature of T-cell antigen recognition is that the process of TCR/peptide-MHC interaction is self-limited by the internalization and degradation of triggered TCR and recruited signaling components. The mechanism of signaling component degradation involves their ubiquitination and targeting for degradation. Yet, the relationship between the ubiquitination process and TCR signaling as well as the cellular localization of TCR-induced ubiquitination are still elusive. In the present work, we visualize for the first time ubiquitination at the TCR signaling area. We show an enrichment of ubiquitin staining in TCR/CD3 caps in T-lymphocytes stimulated by anti-CD3 antibodies. Remarkably, we also show the recruitment of the ubiquitin ligase Cbl-b and a significant ubiquitination at the immunological synapse in antigen-stimulated T-cells. Our results identify the immunological synapse as the cellular area where TCR-induced protein ubiquitination occurs. They imply that the synapse is a specialized site where the activation process is not only triggered, but also controlled via ubiquitination of signaling actors.


Assuntos
Células Apresentadoras de Antígenos/metabolismo , Ativação Linfocitária/fisiologia , Linfócitos T/metabolismo , Ubiquitina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células Apresentadoras de Antígenos/imunologia , Humanos , Ativação Linfocitária/imunologia , Proteínas Proto-Oncogênicas c-cbl , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T/imunologia , Ubiquitina-Proteína Ligases/metabolismo
7.
Immunity ; 22(2): 185-94, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15723807

RESUMO

Helper T cells discriminate among different antigen-presenting cells to provide their help in a selective fashion. The molecular mechanisms leading to this exquisite selectivity are still elusive. Here, we demonstrate that immunological synapses are dynamic and adaptable structures allowing T cells to communicate with multiple cells. We show that T cells can form simultaneous immunological synapses with cells presenting different levels of antigenic ligands but eventually polarize toward the strongest stimulus. Remarkably, living T cells form discrete foci of signal transduction of different intensities during the interaction with different antigen-presenting cells and rapidly relocate TCR and Golgi apparatus toward the cell providing the strongest stimulus. Our results illustrate that, although T cell activation requires sustained signaling, T cells are capable of rapid synapse remodeling and swift polarization responses. The combination of sustained signaling with preferential and rapid polarization provides a mechanism for the high sensitivity and selectivity of T cell responses.


Assuntos
Polaridade Celular , Junções Intercelulares/metabolismo , Linfócitos T/citologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/citologia , Células Apresentadoras de Antígenos/imunologia , Antígenos CD2/imunologia , Antígenos CD2/metabolismo , Antígenos CD58/imunologia , Antígenos CD58/metabolismo , Linhagem Celular , Humanos , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade por Substrato , Linfócitos T/metabolismo
8.
Immunity ; 22(1): 71-80, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15664160

RESUMO

Vgamma9Vdelta2 T lymphocytes, a major gammadelta T lymphocyte subset in humans, display cytolytic activity against various tumor cells upon recognition of yet uncharacterized structures. Here, we show that an entity related to the mitochondrial F1-ATPase is expressed on tumor cell surface and promotes tumor recognition by Vgamma9Vdelta2 T cells. When immobilized, purified F1-ATPase induces selective activation of this lymphocyte subset. The Vgamma9Vdelta2 T cell receptors (TCR) and the F1-ATPase also bind a delipidated form of apolipoprotein A-I (apo A-I), as demonstrated by surface plasmon resonance. Moreover, the presence of apo A-I in the culture medium is required for optimal activation of Vgamma9Vdelta2 T cells by tumors expressing F1-ATPase. This study thus describes an unanticipated tumor recognition mechanism by Vgamma9Vdelta2 lymphocytes and a possible link between gammadelta T cell immunity and lipid metabolism.


Assuntos
Apolipoproteína A-I/metabolismo , Neoplasias/imunologia , ATPases Translocadoras de Prótons/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Humanos , Imobilização , Células Jurkat , Cinética , Ligantes , Ativação Linfocitária , Ligação Proteica , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Ressonância de Plasmônio de Superfície , Propriedades de Superfície , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Células Tumorais Cultivadas
9.
Proc Natl Acad Sci U S A ; 100(24): 14145-50, 2003 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-14610278

RESUMO

Activation of biological functions in T lymphocytes is determined by the molecular dynamics occurring at the T cell/opposing cell interface. In the present study, a central question of cytotoxic T lymphocyte (CTL) biology was studied at the single-cell level: can two distinct activation thresholds for cytotoxicity and cytokine production be explained by intercellular molecular dynamics between CTLs and targets? In this study, we combine morphological approaches with numerical analysis, which allows us to associate specific patterns of calcium mobilization with different biological responses. We show that CTLs selectively activated to cytotoxicity lack a mature immunological synapse while exhibiting a low threshold polarized secretion of lytic granules and spike-like patterns of calcium mobilization. This finding is contrasted by fully activated CTLs, which exhibit a mature immunological synapse and smooth and sustained calcium mobilization. Our results indicate that intercellular molecular dynamics and signaling characteristics allow the definition of two activation thresholds in individual CTLs: one for polarized granule secretion (lytic synapse formation) and the other for cytokine production (stimulatory synapse formation).


Assuntos
Linfócitos T Citotóxicos/imunologia , Sinalização do Cálcio , Adesão Celular/imunologia , Linhagem Celular , Membrana Celular/imunologia , Polaridade Celular , Citocinas/biossíntese , Citotoxicidade Imunológica , Humanos , Junções Intercelulares/imunologia , Interferon gama/biossíntese , Ativação Linfocitária , Glicoproteínas de Membrana/biossíntese , Perforina , Proteínas Citotóxicas Formadoras de Poros , Vesículas Secretórias/imunologia , Linfócitos T Citotóxicos/fisiologia
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