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1.
J Biol Chem ; 286(45): 39153-63, 2011 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-21937446

RESUMO

Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Depending on their maturation status, they prime T cells to induce adaptive immunity or tolerance. DCs express CD155, an immunoglobulin-like receptor binding CD226 present on T and natural killer (NK) cells. CD226 represents an important co-stimulator during T cell priming but also serves as an activating receptor on cytotoxic T and NK cells. Here, we report that cells of the T and NK cell lineage of CD155(-/-) mice express markedly elevated protein levels of CD226 compared with wild type (WT). On heterozygous CD155(+/-) T cells, CD226 up-regulation is half-maximal, implying an inverse gene-dosis effect. Moreover, CD226 up-regulation is independent of antigen-driven activation because it occurs already in thymocytes and naïve peripheral T cells. In vivo, neutralizing anti-CD155 antibody elicits up-regulation of CD226 on T cells demonstrating, that the observed modulation can be triggered by interrupting CD155-CD226 contacts. Adoptive transfers of WT or CD155(-/-) T cells into CD155(-/-) or WT recipients, respectively, revealed that CD226 modulation is accomplished in trans. Analysis of bone marrow chimeras showed that regulators in trans are of hematopoietic origin. We demonstrate that DCs are capable of manipulating CD226 levels on T cells in vivo but not in vitro, suggesting that the process of T cells actively scanning antigen-presenting DCs inside secondary lymphoid organs is required for CD226 modulation. Hence, a CD226 level divergent from WT may be exploited as a sensor to detect abnormal DC/T-cell cross-talk as illustrated for T cells in mice lacking CCR7.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Linfonodos/imunologia , Linfócitos T/imunologia , Regulação para Cima/imunologia , Transferência Adotiva , Animais , Anticorpos Neutralizantes/farmacologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/genética , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Linfonodos/citologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptores CCR7/genética , Receptores CCR7/imunologia , Receptores CCR7/metabolismo , Receptores Virais/antagonistas & inibidores , Receptores Virais/genética , Receptores Virais/imunologia , Receptores Virais/metabolismo , Linfócitos T/citologia , Linfócitos T/metabolismo , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
2.
J Immunol ; 184(4): 1681-9, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-20048123

RESUMO

During their final maturation in the medulla, semimature single-positive (SP) thymocytes downregulate activation markers and subsequently exit into the periphery. Although semimature CD4(+) SP cells are sensitive to negative selection, the timing of when negative selection occurs in the CD8 lineage remains elusive. We show that the abundance of terminally matured CD8(+) SP cells in adult thymus is modulated by the genetic background. Moreover, in BALB/c mice, the frequency of terminally matured CD8(+) SP cells, but not that of CD4(+) SP cells present in thymus, varies depending on age. In mice lacking expression of the adhesion receptor CD155, a selective deficiency of mature CD8(+) SP thymocytes was observed, emerging first in adolescent animals at the age when these cells start to accumulate in wild-type thymus. Evidence is provided that the mature cells emigrate prematurely when CD155 is absent, cutting short their retention time in the medulla. Moreover, in nonmanipulated wild-type mice, semimature CD8(+) SP thymocytes are subjected to negative selection, as reflected by the diverging TCR repertoires present on semimature and mature CD8(+) T cells. In CD155-deficient animals, a shift was found in the TCR repertoire displayed by the pool of CD8(+) SP cells, demonstrating that CD155 is involved in negative selection.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Senescência Celular/imunologia , Receptores Virais/fisiologia , Timo/citologia , Timo/imunologia , Envelhecimento/genética , Envelhecimento/imunologia , Animais , Apoptose/genética , Apoptose/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Movimento Celular/genética , Senescência Celular/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , Receptores Virais/deficiência , Receptores Virais/genética , Timo/metabolismo
3.
Eur J Immunol ; 39(11): 3160-70, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19688744

RESUMO

The secondary humoral immune response is characterized by plasma B cells secreting isotype-switched and affinity-matured antibodies. The efficient generation of plasma B cells in the GC depends on the presence of follicular helper T (T(FH)) cells, a cell type thought to arise from naive CD4-positive T cells by a hitherto unresolved differentiation pathway. Mice deficient for CD155, an adhesion receptor of the immunoglobulin superfamily, are impaired to mount a secondary humoral immune response upon oral administration of antigen, while the primary IgM response is unaffected. Here, we show that mice lacking CD155 harbor significantly reduced numbers of T(FH) cells in their Peyer's patches. This was paralleled by a decreased frequency of T(FH) cells in the GC. Moreover, the CD155 ligand CD226, which is involved in T-cell activation, is down-regulated during T(FH) cell differentiation, resulting in a complete absence of CD226 on those T(FH) cells residing in the GC. Concurrently, the expression of TIGIT/WUCAM, a newly discovered CD155 ligand, is induced in T(FH) cells. Thus, these cells replace an activating by a putative inhibitory CD155-binding partner during their differentiation.


Assuntos
Imunomodulação/imunologia , Ativação Linfocitária/imunologia , Nódulos Linfáticos Agregados/imunologia , Receptores Virais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/imunologia , Diferenciação Celular/imunologia , Separação Celular , Feminino , Citometria de Fluxo , Centro Germinativo/citologia , Centro Germinativo/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Nódulos Linfáticos Agregados/citologia , Receptores Imunológicos/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T Auxiliares-Indutores/citologia
4.
J Leukoc Biol ; 86(1): 91-101, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19380711

RESUMO

The adhesion receptor CD226 (DNAM-1) is a member of the Ig superfamily possessing two extracellular V-like domains. In humans, CD226 was shown to be expressed by NK as well as T cells. During T cell priming, CD226-mediated costimulatory signals may skew the subsequent differentiation into the Th1 pathway. In addition, CD226 expressed on NK and cytotoxic T cells is engaged by its counter-receptor CD155, present on target cells, thereby triggering their elimination. We established mAb specifically recognizing mCD226, demonstrating that CD226 is expressed by precursor and mature but not developing T cells. In contrast, NK cells are distinguished by a rather heterogeneous CD226 expression profile. In addition, expression of CD226 appears coupled to that of other NK cell receptors, as high expression of CD226 was found to correlate with decreased proportions of Ly49D and H positive NK cells. Upon injection into mice, the anti-CD226 antibodies caused selective depletion of CD8(+) T cells. Moreover, these antibodies as well as a naturally occurring CD226 splice variant lacking the outermost V-like domain were instrumental in determining that CD226 adheres to CD155 via its first domain. In addition, antibodies were identified as capable of blocking the CD226/CD155 interaction and to prevent NK-driven killing of immature DC. CD226 is thus the first mNK receptor identified to be essential for the elimination of this particular cell type.


Assuntos
Antígenos de Diferenciação de Linfócitos T/imunologia , Células Dendríticas/citologia , Células Matadoras Naturais/imunologia , Receptores Virais/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Diferenciação de Linfócitos T/análise , Antígenos de Diferenciação de Linfócitos T/metabolismo , Sítios de Ligação , Citotoxicidade Imunológica , Regulação da Expressão Gênica/imunologia , Camundongos , Ligação Proteica/imunologia , Receptores Virais/metabolismo
5.
J Biol Chem ; 284(4): 2235-44, 2009 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-19056733

RESUMO

The adhesion receptor CD96 (TACTILE) is a transmembrane glycoprotein possessing three extracellular immunoglobulin-like domains. Among peripheral blood cells, CD96 is expressed on T cells as well as NK cells and a subpopulation of B cells. A possible function of this receptor in NK cell-mediated killing activities was suggested recently. Moreover, CD96 was described as a tumor marker for T-cell acute lymphoblastic leukemia and acute myeloid leukemia. CD96 binds to CD155 (poliovirus receptor) and nectin-1, an adhesion receptor related to CD155. Here we report that human but not mouse CD96 is expressed in two splice variants possessing either an I-like (variant 1) or V-like (variant 2) second domain. With the notable exception of an AML tumor sample, variant 2 predominates in all the CD96-expressing cell types and tissues examined. Using chimeric human/murine CD96 receptors, we show that the interaction with its ligands is mediated via the outermost V-like domain. In contrast to mouse, however, the binding of human CD96 to CD155 is sensitive to the characteristics of the two downstream domains. This is illustrated by a significantly weaker CD96/CD155 interaction mediated by variant 1 when compared with variant 2. Moreover, recent evidence suggested that mutations in human CD96 correlate with the occurrence of a rare form of trigonocephaly. One such mutation causing a single amino acid exchange in the third domain of human CD96 decreased the capacity of both variants to bind to CD155 considerably, suggesting that a CD96-driven adhesion to CD155 may be crucial in developmental processes.


Assuntos
Processamento Alternativo/genética , Antígenos CD/imunologia , Antígenos CD/metabolismo , Imunoglobulinas/imunologia , Imunoglobulinas/metabolismo , Receptores Virais/imunologia , Receptores Virais/metabolismo , Sequência de Aminoácidos , Animais , Antígenos CD/química , Antígenos CD/genética , Linhagem Celular , Humanos , Imunoglobulinas/genética , Ligantes , Camundongos , Dados de Sequência Molecular , Mutação/genética , Ligação Proteica , Dobramento de Proteína , Receptores Virais/genética , Alinhamento de Sequência
6.
Eur J Immunol ; 37(8): 2214-25, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17621371

RESUMO

CD155, originally known as the cellular receptor for poliovirus, is the founding member of a subfamily of immunoglobulin-like adhesion receptors. Apart from its function in establishing adherens junctions between contacting epithelial cells, the engagement of CD155 with two recently identified ligands, CD226 and CD96, mediates immunologically relevant processes such as NK cell-driven killing of tumor cells in humans. Here we report on the generation and immunological analysis of mice constitutively deficient of CD155. Moreover, the expression profile of CD155 on hematopoietic cells has been determined using newly established antibodies. CD155-deficient mice develop normally without displaying an overt phenotype. However, the animals are distinguished by distinct deficits in the development of a regular humoral immune response. Whereas systemic challenges revealed no differences, orally administered antigen evoked less efficient IgG and IgA antibody responses despite of normal IgM titers when compared to wild-type mice. Therefore, CD155 may assist in an efficient humoral immune response generated within the intestinal immune system.


Assuntos
Anticorpos Monoclonais/imunologia , Formação de Anticorpos , Antígenos/administração & dosagem , Proteínas de Membrana/imunologia , Receptores Virais/imunologia , Administração Oral , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas de Membrana/deficiência , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/metabolismo , Plasmócitos/imunologia , Plasmócitos/metabolismo , Ratos , Receptores Virais/deficiência , Linfócitos T/imunologia , Linfócitos T/metabolismo
7.
Endocrinology ; 146(4): 1701-6, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15661862

RESUMO

Recent genetic analysis in several patients presenting a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels have revealed mutations or deletions in the gene of the monocarboxylate transporter 8 (MCT8). Because in vitro MCT8 functions as a TH transporter, the complex clinical picture of these patients indicated an important role for MCT8 in TH-dependent processes of brain development. To provide a clue to the cellular function of MCT8 in brain, we studied the expression of MCT8 mRNA in the murine central nervous system by in situ hybridization histochemistry. In addition to the choroid plexus structures, the highest transcript levels were found in neo- and allocortical regions (e.g. olfactory bulb, cerebral cortex, hippocampus, and amygdala), moderate signal intensities in striatum and cerebellum, and low levels in a few neuroendocrine nuclei. Colocalization studies revealed that MCT8 is predominantly expressed in neurons. Together with the spatiotemporal expression pattern of MCT8 during the perinatal period, these results strongly indicate that MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells.


Assuntos
Encéfalo/metabolismo , Proteínas de Transporte/genética , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/fisiologia , Neurônios/metabolismo , Transtornos Psicomotores/genética , RNA Mensageiro/análise , Hormônios Tireóideos/metabolismo , Animais , Feminino , Humanos , Iodeto Peroxidase/genética , Masculino , Camundongos , Proteínas de Transporte de Cátions Orgânicos/genética , Simportadores , Iodotironina Desiodinase Tipo II
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