RESUMEN

Deregulated nuclear factor kappaB (NF-kappaB) activation plays an important role in inflammation and tumorigenesis. ABIN proteins have been characterized as negative regulators of NF-kappaB signaling. However, their mechanism of NF-kappaB inhibition remained unclear. With the help of a yeast two-hybrid screen, we identified ABIN proteins as novel ubiquitin-interacting proteins. The minimal ubiquitin-binding domain (UBD) corresponds to the ABIN homology domain 2 (AHD2) and is highly conserved in ABIN-1, ABIN-2 and ABIN-3. Moreover, this region is also present in NF-kappaB essential modulator/IkappaB kinase gamma (NEMO/IKKgamma) and the NEMO-like protein optineurin, and is therefore termed UBD in ABIN proteins and NEMO (UBAN). Nuclear magnetic resonance studies of the UBAN domain identify it as a novel type of UBD, with the binding surface on ubiquitin being significantly different from the binding surface of other UBDs. ABIN-1 specifically binds ubiquitinated NEMO via a bipartite interaction involving its UBAN and NEMO-binding domain. Mutations in the UBAN domain led to a loss of ubiquitin binding and impaired the NF-kappaB inhibitory potential of ABINs. Taken together, these data illustrate an important role for ubiquitin binding in the negative regulation of NF-kappaB signaling by ABINs and identify UBAN as a novel UBD.

Asunto(s)

Proteínas de Unión al ADN/fisiología , FN-kappa B/antagonistas & inhibidores , Ubiquitina/metabolismo , Sitios de Unión , Línea Celular , Proteínas de Unión al ADN/química , Humanos , FN-kappa B/fisiología , Estructura Terciaria de Proteína , Transducción de Señal , Técnicas del Sistema de Dos Híbridos

Asunto(s)

Regulación de la Expresión Génica/fisiología , Glucocorticoides/fisiología , Linfocitos T/fisiología , Animales , Humanos , Receptores de Interleucina-7/genética , Receptores de Interleucina-7/fisiología , Factores de Transcripción/genética , Factores de Transcripción/fisiología

RESUMEN

The immunosuppressive effects of glucocorticoids arise largely by inhibition of cytokine gene expression, which has been ascribed to interference between the glucocorticoid receptor and transcription factors such as AP-1 and NF-kappa B as well as by competition for common coactivators. Here we show that glucocorticoid-induced inhibition of interleukin-2 mRNA expression in activated normal T cells required new protein synthesis, suggesting that this phenomenon is secondary to expression of glucocorticoid-regulated genes. One of the most prominent glucocorticoid-induced genes is glucocorticoid-induced leucine zipper (GILZ), which has been reported to inhibit activation-induced up-regulation of Fas ligand (FasL) mRNA. Indeed, transient expression of GILZ in Jurkat T cells blocked induction of a reporter construct driven by the FasL promoter. This could be accounted for by GILZ-mediated inhibition of Egr-2 and Egr-3, NFAT/AP-1-inducible transcription factors that bind a regulatory element in the FasL promoter and up-regulate FasL expression. GILZ also potently inhibited AP-1-driven and IL-2 promoter-driven reporter constructs, and recombinant GILZ specifically interacted with c-Fos and c-Jun in vitro and inhibited the binding of active AP-1 to its target DNA. Whereas homodimerization of GILZ required the presence of its leucine zipper, the interaction with c-Fos and c-Jun occurred through the N-terminal 60-amino acid region of GILZ. Thus, GILZ represents a glucocorticoid-induced gene product that can inhibit a variety of activation-induced events, at least in part by direct interference with AP-1, and is therefore a candidate for a mediator of glucocorticoid-induced immunosuppression.

Asunto(s)

Dexametasona/farmacología , Regulación de la Expresión Génica/inmunología , Glucocorticoides/farmacología , Interleucina-2/genética , Proteínas Nucleares , Factor de Transcripción AP-1/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz , Proteína 3 de la Respuesta de Crecimiento Precoz , Proteína Ligando Fas , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Células Jurkat , Leucina Zippers , Glicoproteínas de Membrana/genética , FN-kappa B/metabolismo , Factores de Transcripción NFATC , Regiones Promotoras Genéticas/efectos de los fármacos , Linfocitos T/inmunología , Factor de Transcripción AP-1/antagonistas & inhibidores , Factores de Transcripción/antagonistas & inhibidores , Transcripción Genética/efectos de los fármacos , Transcripción Genética/inmunología

Asunto(s)

Apoptosis/fisiología , Línea Celular , Células Tumorales Cultivadas , Animales , Humanos , Células Jurkat , Células PC12 , Ratas

RESUMEN

CD4+ T cells die in individuals infected with HIV, either as a result of direct HIV infection or as uninfected "innocent bystanders". Possible mechanisms for bystander killing include generation of viral products such as Tat or gp120 and expression of death receptor ligands, such as FasL, that engage functional death receptors on uninfected cells. This review covers the sometimes conflicting in vitro and ex vivo studies that address these possible mechanisms of HIV-associated cell death. It is an intriguing possibility that manipulation of cell death processes, to decrease bystander death or increase death of infected cells, in patients infected with HIV might provide a useful adjunct to antiretroviral therapy.

Asunto(s)

Apoptosis , Infecciones por VIH/patología , VIH-1 , Humanos , Linfocitos T/patología , Replicación Viral

Asunto(s)

Glucocorticoides/metabolismo , Linfocitos T/metabolismo , Timo/metabolismo , Animales , Diferenciación Celular , Reordenamiento Génico de Linfocito T , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta , Linfocitos T/citología , Timo/citología

RESUMEN

Glucocorticoids are small lipophilic compounds that mediate their many biological effects by binding an intracellular receptor (GR) that, in turn, translocates to the nucleus and directly or indirectly regulates gene transcription. Perhaps the most recognized biologic effect of glucocorticoids on peripheral T cells is immunosuppression, which is due to inhibition of expression of a wide variety of activationinduced gene products. Glucocorticoids have also been implicated in Th lineage development (favoring the generation of Th2 cells) and, by virtue of their downregulation of fasL expression, the inhibition of activation-induced T cell apoptosis. Glucocorticoids are also potent inducers of apoptosis, and even glucocorticoid concentrations achieved during a stress response can cause the death of CD4(+)CD8(+ )thymocytes. Perhaps surprisingly, thymic epithelial cells produce glucocorticoids, and based upon in vitro and in vivo studies of T cell development it has been proposed that these locally produced glucocorticoids participate in antigen-specific thymocyte development by inhibiting activation-induced gene transcription and thus increasing the TCR signaling thresholds required to promote positive and negative selection. It is anticipated that studies in animals with tissue-specific GR-deficiency will further elucide how glucocorticoids affect T cell development and function.

Asunto(s)

Glucocorticoides/inmunología , Linfocitos T/inmunología , Animales , Apoptosis/inmunología , División Celular , Humanos , Receptores de Glucocorticoides/inmunología , Linfocitos T/citología , Timo/citología , Timo/inmunología

RESUMEN

To determine why proteasome inhibitors prevent thymocyte death, we examined whether proteasomes degrade anti-apoptotic molecules in cells induced to undergo apoptosis. The c-IAP1 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wild-type c-IAP1, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wild-type XIAP. Autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.

Asunto(s)

Apoptosis , Cisteína Endopeptidasas/metabolismo , Ligasas/metabolismo , Complejos Multienzimáticos/metabolismo , Proteínas/metabolismo , Linfocitos T/metabolismo , Animales , Células Cultivadas , Dexametasona/farmacología , Etopósido/farmacología , Hibridomas , Proteínas Inhibidoras de la Apoptosis , Ratones , Ratones Endogámicos C57BL , Complejo de la Endopetidasa Proteasomal , Estructura Terciaria de Proteína , Proteínas/química , Proteínas/genética , Proteínas Recombinantes de Fusión/metabolismo , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Timo/citología , Transfección , Ubiquitina-Proteína Ligasas , Ubiquitinas/metabolismo , Proteína Inhibidora de la Apoptosis Ligada a X

RESUMEN

We have proposed that glucocorticoids antagonize TCR-mediated activation and influence which TCR avidities result in positive or negative selection. We now analyze the immune response of mice whose thymocytes express antisense transcripts to the glucocorticoid receptor (TKO mice). TKO mice responded normally to the complex antigen PPD but were proliferative nonresponders to pigeon cytochrome c 81-104 (PCC), having a large decrease in the frequency of PCC-responsive CD4+ T cells. Unlike wild-type T cells, few TKO T cells in PCC-specific cell lines expressed V alpha11+Vbeta3+. Furthermore, for naive CD4+ T cells from unimmunized TKO mice, the frequencies of many of the molecular features common to the CDR3 regions of PCC-responsive V alpha11+Vbeta3+ cells were substantially decreased. Thus, thymocyte glucocorticoid hyporesponsiveness resulted in loss of cells capable of responding to PCC, corresponding to an antigen-specific "hole" in the T cell repertoire.

Asunto(s)

Glucocorticoides/fisiología , Linfocitos T/inmunología , Animales , Línea Celular , Grupo Citocromo c/inmunología , Grupo Citocromo c/farmacología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Glucocorticoides/biosíntesis , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/inmunología , Linfocitos T/efectos de los fármacos , Timo/citología

RESUMEN

The critical function of NFAT proteins in maintaining lymphoid homeostasis was revealed in mice lacking both NFATp and NFAT4 (DKO). DKO mice exhibit increased lymphoproliferation, decreased activation-induced cell death, and impaired induction of FasL. The transcription factors Egr2 and Egr3 are potent activators of FasL expression. Here we find that Egr2 and Egr3 are NFAT target genes. Activation of FasL occurs via the NFAT-dependent induction of Egr3, as demonstrated by the ability of exogenously provided NFATp to restore Egr-dependent FasL promoter activity in DKO lymph node cells. Further, Egr3 expression is enriched in Th1 cells, suggesting a molecular basis for the known preferential expression of FasL in the Th1 versus Th2 subset.

Asunto(s)

Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Glicoproteínas de Membrana/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Activación Transcripcional , Animales , Sitios de Unión , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Extractos Celulares , Núcleo Celular/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/fisiología , Proteína 2 de la Respuesta de Crecimiento Precoz , Proteína 3 de la Respuesta de Crecimiento Precoz , Proteína Ligando Fas , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Factores de Transcripción NFATC , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Regiones Promotoras Genéticas , Células TH1/citología , Células TH1/metabolismo , Células Th2/citología , Células Th2/metabolismo , Factores de Transcripción/fisiología

Asunto(s)

Glucocorticoides/fisiología , Subgrupos de Linfocitos T/citología , Timo/efectos de los fármacos , Animales , Antígenos CD5/biosíntesis , Supresión Clonal/efectos de los fármacos , Glucocorticoides/farmacología , Humanos , Activación de Linfocitos/efectos de los fármacos , Metirapona/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Técnicas de Cultivo de Órganos , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Glucocorticoides/deficiencia , Receptores de Glucocorticoides/efectos de los fármacos , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/fisiología , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/efectos de los fármacos , Timo/citología , Timo/embriología , Timo/inmunología

RESUMEN

Gadd45a-null mice generated by gene targeting exhibited several of the phenotypes characteristic of p53-deficient mice, including genomic instability, increased radiation carcinogenesis and a low frequency of exencephaly. Genomic instability was exemplified by aneuploidy, chromosome aberrations, gene amplification and centrosome amplification, and was accompanied by abnormalities in mitosis, cytokinesis and growth control. Unequal segregation of chromosomes due to multiple spindle poles during mitosis occurred in several Gadd45a -/- cell lineages and may contribute to the aneuploidy. Our results indicate that Gadd45a is one component of the p53 pathway that contributes to the maintenance of genomic stability.

Asunto(s)

Proteínas/genética , Animales , Apoptosis/genética , Ciclo Celular/genética , Ciclo Celular/fisiología , División Celular/genética , Transformación Celular Neoplásica/genética , Senescencia Celular , Centrosoma/metabolismo , Embrión de Mamíferos/citología , Femenino , Fibroblastos/citología , Fibroblastos/fisiología , Fase G1 , Rayos gamma/efectos adversos , Eliminación de Gen , Genes ras/genética , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neoplasias/etiología , Neoplasias/genética , Fenotipo , Proteínas/fisiología , Hiperplasia del Timo/genética , Hiperplasia del Timo/patología , Proteinas GADD45

RESUMEN

In attempting to produce the intracellular portion of human Fas (IC175 - 319) as a GST-fusion protein we found that expression of GST-IC175 - 319, but not GST alone or GST-IC231 - 298 (containing the Fas death domain), rapidly caused the death of host E. coli cells. Expression of GST-IC175 - 319 with a single amino acid substitution (V238N) corresponding to the mouse lprcg mutation, or E245A, which abolishes the ability of Fas to self-associate, did not kill bacteria. Deletional analysis identified a 20-amino acids region (Asp210 - Lys230) as essential for the killing activity, and introduction of a single amino acid substitution (T225P) in this 20 amino acid region markedly decreased the ability of Fas- IC175 - 319 to cause bacterial death. These data indicate that Fas can deliver a death signal in prokaryotic organisms by a means that shares some features with eukaryotic cells, and raise the possibility that certain mechanisms leading to programmed cell death may be conserved from bacteria to mammalian cells.

Asunto(s)

Escherichia coli , Receptor fas/farmacología , Animales , Sitios de Unión , Humanos , Líquido Intracelular , Ratones , Mutación Puntual , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/farmacología , Receptor fas/genética

Asunto(s)

Antígenos Comunes de Leucocito/metabolismo , Familia-src Quinasas/metabolismo , Animales , Humanos , Modelos Biológicos , Fosforilación

RESUMEN

Selection processes in the thymus eliminate nonfunctional or harmful T cells and allow the survival of those cells with the potential to recognize Ag in association with self-MHC-encoded molecules (Ag/MHC). We have previously demonstrated that thymus-derived glucocorticoids antagonize TCR-mediated deletion, suggesting a role for endogenous thymic glucocorticoids in promoting survival of thymocytes following TCR engagement. Consistent with this hypothesis, we now show that inhibition of thymus glucocorticoid biosynthesis causes an increase in thymocyte apoptosis and a decrease in recovery that are directly proportional to the number of MHC-encoded molecules present and, therefore, the number of ligands available for TCR recognition. Expression of CD5 on CD4+CD8+ thymocytes, an indicator of TCR-mediated activation, increased in a TCR- and MHC-dependent manner when corticosteroid production or responsiveness was decreased. These results indicate that thymus-derived glucocorticoids determine where the window of thymocyte selection occurs in the TCR avidity spectrum by dampening the biological consequences of TCR occupancy and reveal that glucocorticoids mask the high percentage of self-Ag/MHC-reactive thymocytes that exist in the preselection repertoire.

Asunto(s)

Glucocorticoides/fisiología , Inmunosupresores/farmacología , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T alfa-beta/fisiología , Linfocitos T/inmunología , Timo/inmunología , Timo/metabolismo , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Autoantígenos/fisiología , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/inmunología , Femenino , Feto , Glucocorticoides/antagonistas & inhibidores , Glucocorticoides/biosíntesis , Inmunosupresores/antagonistas & inhibidores , Activación de Linfocitos/efectos de los fármacos , Complejo Mayor de Histocompatibilidad/efectos de los fármacos , Complejo Mayor de Histocompatibilidad/fisiología , Masculino , Metirapona/farmacología , Ratones , Ratones Endogámicos C57BL , Técnicas de Cultivo de Órganos , Receptores de Antígenos de Linfocitos T alfa-beta/antagonistas & inhibidores , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Timo/citología

RESUMEN

While Jun/Fos-containing transcription factors are known to be necessary for many TCR-mediated events in mature T cells, relatively little is known about their roles in thymocyte development. We have generated transgenic mice that express a trans-dominant-negative mutant of c-Jun (TAM-67) specifically in thymocytes. Expression of TAM-67 inhibited the up-regulation of AP-1-responsive genes such as c-jun and IL-2 in stimulated thymocytes from transgenic mice. In addition, altered thymocyte development in TAM-67-expressing mice was revealed by a decrease in thymic cellularity ( approximately 50%) which could be accounted for primarily by a reduction in the number of CD4(+)CD8(+) thymocytes, a large percentage of which retained CD25. The decrease in the number of CD4(+)CD8(+) thymocytes did not appear to be due to an enhanced rate of apoptosis but rather to a decrease in the number of CD4(-)CD8(-)CD25(-) cells in the S + G(2)/M stages of the cell cycle. These results indicate that Jun/Fos-containing transcription factors promote the proliferative burst that accompanies the transition from the CD4(-)CD8(-) to the CD4(+)CD8(+) stage of thymocyte development.

Asunto(s)

Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Genes jun , Proteínas Proto-Oncogénicas c-jun/fisiología , Subgrupos de Linfocitos T/citología , Timo/citología , Factor de Transcripción AP-1/metabolismo , Animales , Ciclo Celular , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Interleucina-2/genética , Interleucina-2/metabolismo , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Noqueados , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-jun/genética , Receptores de Interleucina-2/metabolismo , Timo/embriología , Factor de Transcripción AP-1/genética , Factores de Transcripción/metabolismo

RESUMEN

A widely accepted model for regulation of the Lck tyrosine kinase is that it is activated by CD45-mediated dephosphorylation of its COOH-terminal negative regulatory tyrosine (Tyr505). Previous work from our laboratory, however, found that despite hyperphosphorylation of Tyr505, the activity of Lck from CD45- T cell lines was actually increased due to hyperphosphorylation of the positive regulatory tyrosine, residue 394. To avoid potential complications introduced by transformed cells, in this study we have characterized the effect of CD45 on Lck activity in normal cells. Lck in thymocytes from CD45-/- mice was hyperphosphorylated on tyrosine residues. Importantly, and in disagreement with the model that CD45 only activates Lck in vivo, the kinase activity of Lck from cells lacking CD45 was substantially increased. These results support a model in which CD45 dephosphorylates both Tyr505 and Tyr394, the net effect in normal thymocytes being a decrease in enzymatic activity.

Asunto(s)

Inhibidores Enzimáticos/farmacología , Antígenos Comunes de Leucocito/fisiología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Linfocitos T/enzimología , Timo/enzimología , Secuencia de Aminoácidos , Animales , Activación Enzimática/inmunología , Citometría de Flujo , Antígenos Comunes de Leucocito/genética , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Fosforilación , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-fyn , Linfocitos T/inmunología , Linfocitos T/metabolismo , Timo/citología , Timo/inmunología , Tirosina/metabolismo

RESUMEN

We previously identified a Fas ligand regulatory element (FLRE) in the Fas ligand (fasL) promoter that binds Egr family proteins and demonstrated that Egr-3 (PILOT) but not Egr-1 (NGFI-A, Krox-24, Tis-8, and Zif-268) induces transcription of fasL. The aberrant CD4(-)CD8(-) T cells from lpr/lpr and gld/gld mice, which have mutations in the genes encoding Fas and FasL, respectively, have an activated phenotype and constitutively express high levels of fasL mRNA, prompting us to ask what role if any the FLRE and Egr family proteins have in this aberrant expression of fasL. Unstimulated MRL-lpr/lpr and C3H-gld/gld CD4(-)CD8(-) T cells constitutively contained high levels of two proteins that bound to the FLRE. Supershift analysis revealed these proteins to be Egr-1 and Egr-2 (Krox-20); Egr-3 was not detected. Activation of normal lymph node cells resulted in increased expression of Egr-1, -2, and -3. As with egr-3, expression of egr-2 was blocked by cyclosporin A. Although overexpressed Egr-1 was ineffective, overexpressed Egr-2 was as potent as Egr-3 in inducing fasL promoter-dependent reporter constructs in T cell hybridomas and HeLa cells, and both up-regulated endogenous fasL mRNA in HeLa cells. FasL-dependent reporter constructs in MRL-lpr/lpr and C3H-gld/gld CD4(-)CD8(-) T cells were constitutively active, and this activity was largely prevented by mutation of the critical Egr family binding element. Thus, Egr-2, in addition to Egr-3, regulates FasL expression in activated normal T cells, and Egr-2 is likely to play a direct role in aberrant fasL up-regulation in lpr/lpr and gld/gld CD4(-)CD8(-) T cells.

Asunto(s)

Proteínas de Unión al ADN/fisiología , Proteínas Inmediatas-Precoces/fisiología , Glicoproteínas de Membrana/biosíntesis , Linfocitos T/metabolismo , Factores de Transcripción/fisiología , Regulación hacia Arriba , Dedos de Zinc/fisiología , Animales , ADN/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteína 1 de la Respuesta de Crecimiento Precoz , Proteína 2 de la Respuesta de Crecimiento Precoz , Proteína 3 de la Respuesta de Crecimiento Precoz , Proteína Ligando Fas , Células HeLa , Humanos , Glicoproteínas de Membrana/genética , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos MRL lpr , Ratones Mutantes , Regiones Promotoras Genéticas , ARN Mensajero/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética

RESUMEN

Bidirectional interactions of both a stimulatory and inhibitory nature occur between the neuroendocrine and the immune systems, and these interactions play an important modulatory role during T-cell ontogeny. Specifically, glucocorticoids potently induce apoptosis in thymocytes and activated T cells, but can also rescue these cells from activation-induced cell death. The objective of this review is to discuss current data on the interactions of the immune system with steroid hormones in the thymus and to describe a model that includes glucocorticoids in the shaping of the peripheral T-cell antigen-specific repertoire and deals with their potential role in the generation of autoimmune disease.

Asunto(s)

Sistema Inmunológico/fisiología , Esteroides/fisiología , Timo/fisiología , Animales , Apoptosis , Glucocorticoides/fisiología , Hormonas Esteroides Gonadales/fisiología , Humanos , Linfocitos T/fisiología

RESUMEN

Apoptosis is the fate of most thymocytes. Many molecules participate in the decision of whether a thymocyte is to live or to die, including cell surface receptors, such as the T cell receptor for antigen, Notch-1, and costimulatory receptors, ligand-regulated nuclear transcription factors such as the glucocorticoid receptor, signaling, and effector proteases, and direct regulators of the apoptotic machinery such IAPs. In this review we discuss recent data concerning these molecules and pathways and their implication for understanding the mechanisms underlying thymocyte death, survival, and the generation of inmmunocompetent T cells.

Asunto(s)

Apoptosis , Linfocitos T/fisiología , Animales , Caspasas/fisiología , Quinasas Ciclina-Dependientes/fisiología , Humanos , Proteínas de la Membrana/fisiología , Quinasas de Proteína Quinasa Activadas por Mitógenos/fisiología , Proteínas/fisiología , Receptores de Antígenos de Linfocitos T/fisiología , Receptores de Glucocorticoides/fisiología , Receptores Notch , Proteína Inhibidora de la Apoptosis Ligada a X