RESUMEN
T cell specificity and function are linked during development, as MHC-II-specific TCR signals generate CD4 helper T cells and MHC-I-specific TCR signals generate CD8 cytotoxic T cells, but the basis remains uncertain. We now report that switching coreceptor proteins encoded by Cd4 and Cd8 gene loci functionally reverses the T cell immune system, generating CD4 cytotoxic and CD8 helper T cells. Such functional reversal reveals that coreceptor proteins promote the helper-lineage fate when encoded by Cd4, but promote the cytotoxic-lineage fate when encoded in Cd8-regardless of the coreceptor proteins each locus encodes. Thus, T cell lineage fate is determined by cis-regulatory elements in coreceptor gene loci and is not determined by the coreceptor proteins they encode, invalidating coreceptor signal strength as the basis of lineage fate determination. Moreover, we consider that evolution selected the particular coreceptor proteins that Cd4 and Cd8 gene loci encode to avoid generating functionally reversed T cells because they fail to promote protective immunity against environmental pathogens.
Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Antígenos CD4/metabolismo , Antígenos CD8/metabolismo , Diferenciación Celular , Linaje de la Célula/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Timo/metabolismoRESUMEN
The T cell antigen receptor (TCR) expressed on thymocytes interacts with self-peptide major histocompatibility complex (pMHC) ligands to signal apoptosis or survival. Here, we found that negative-selection ligands induced thymocytes to exert forces on the TCR and the co-receptor CD8 and formed cooperative TCR-pMHC-CD8 trimolecular 'catch bonds', whereas positive-selection ligands induced less sustained thymocyte forces on TCR and CD8 and formed shorter-lived, independent TCR-pMHC and pMHC-CD8 bimolecular 'slip bonds'. Catch bonds were not intrinsic to either the TCR-pMHC or the pMHC-CD8 arm of the trans (cross-junctional) heterodimer but resulted from coupling of the extracellular pMHC-CD8 interaction to the intracellular interaction of CD8 with TCR-CD3 via associated kinases to form a cis (lateral) heterodimer capable of inside-out signaling. We suggest that the coupled trans-cis heterodimeric interactions form a mechanotransduction loop that reinforces negative-selection signaling that is distinct from positive-selection signaling in the thymus.
Asunto(s)
Mecanotransducción Celular/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Timocitos/inmunología , Timo/inmunología , Animales , Supresión Clonal/inmunología , Ratones , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Timocitos/metabolismoRESUMEN
Major histocompatibility complex class I (MHC I) positive selection of CD8+ T cells in the thymus requires that T cell antigen receptor (TCR) signaling end in time for cytokines to induce Runx3d, the CD8-lineage transcription factor. We examined the time required for these events and found that the overall duration of positive selection was similar for all CD8+ thymocytes in mice, despite markedly different TCR signaling times. Notably, prolonged TCR signaling times were counter-balanced by accelerated Runx3d induction by cytokines and accelerated differentiation into CD8+ T cells. Consequently, lineage errors did not occur except when MHC I-TCR signaling was so prolonged that the CD4-lineage-specifying transcription factor ThPOK was expressed, preventing Runx3d induction. Thus, our results identify a compensatory signaling mechanism that prevents lineage-fate errors by dynamically modulating Runx3d induction rates during MHC I positive selection.
Asunto(s)
Linfocitos T CD8-positivos/fisiología , Selección Clonal Mediada por Antígenos , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Timo/inmunología , Animales , Diferenciación Celular , Linaje de la Célula , Células Cultivadas , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Citocinas/metabolismo , Antígenos de Histocompatibilidad Clase I/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Factores de TranscripciónRESUMEN
It has recently become clear that signals mediated by members of the TNFR superfamily, including lymphotoxin-ß receptor (LTßR), receptor activator for NF-κB (RANK), and CD40, play essential roles in organizing the integrity of medullary thymic epithelial cells (mTECs) required for the establishment of self-tolerance. However, details of the mechanism responsible for the unique and cooperative action of individual and multiple TNFR superfamily members during mTEC differentiation still remain enigmatic. In this study, we show that the LTßR signal upregulates expression of RANK in the thymic stroma, thereby promoting accessibility to the RANK ligand necessary for mTEC differentiation. Cooperation between the LTßR and RANK signals for optimal mTEC differentiation was underscored by the exaggerated defect of thymic organogenesis observed in mice doubly deficient for these signals. In contrast, we observed little cooperation between the LTßR and CD40 signals. Thus, the LTßR signal exhibits a novel and unique function in promoting RANK activity for mTEC organization, indicating a link between thymic organogenesis mediated by multiple cytokine signals and the control of autoimmunity.
Asunto(s)
Diferenciación Celular/inmunología , Células Epiteliales/citología , Receptor beta de Linfotoxina/metabolismo , Organogénesis , Receptor Activador del Factor Nuclear kappa-B/biosíntesis , Transducción de Señal , Timo/embriología , Animales , Antígenos CD40/metabolismo , Embrión de Mamíferos , Citometría de Flujo , Expresión Génica , Regulación de la Expresión Génica , Inmunohistoquímica , Ratones , Ratones Noqueados , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Autotolerancia/inmunología , Timo/citología , Timo/metabolismoRESUMEN
NF-κB-inducing kinase (NIK) plays critical roles in the development of lymph nodes and Peyer's patches, and microarchitecture of the thymus and spleen via NF-κB activation. Alymphoplasia (aly/aly) mice have a point mutation in the NIK gene that causes a defect in the activation of an NF-κB member RelB. Here, we developed a novel method to determine the aly mutation by genetic typing using PCR. This method facilitated the easy establishment of a congeneic aly/aly mouse line. Indeed, we generated a mouse line with aly mutation on a BALB/cA background (BALB/cA-aly/aly). BALB/cA-aly/aly mice showed significant splenomegaly with extramedullary hemopoiesis, which was not significant in aly/aly mice on a C57BL/6 background. Interestingly, the splenomegaly and extramedullary hemopoiesis caused by the aly mutation was gender-dependent. These data together with previous reports on extramedullary hemopoiesis in RelB-deficient mice suggest that NIK-RelB signaling may be involved in the suppression of extramedullary hemopoiesis in adult mice.
Asunto(s)
Regulación Enzimológica de la Expresión Génica , Hematopoyesis Extramedular/genética , Proteínas Serina-Treonina Quinasas/genética , Factor de Transcripción ReIB/metabolismo , Animales , Secuencia de Bases , Femenino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Mutación , Bazo/fisiología , Esplenomegalia/genética , Factor de Transcripción ReIB/genética , Quinasa de Factor Nuclear kappa BRESUMEN
Medullary thymic epithelial cells (mTECs) are essential for thymic negative selection to prevent autoimmunity. Previous studies show that mTEC development is dependent on the signal transducers TRAF6 and NIK. However, the downstream target genes of signals controlled by these molecules remain unknown. We performed a microarray analysis on mRNAs down-regulated by deficiencies in TRAF6 or functional NIK in an in vitro organ culture of fetal thymic stromata (2DG-FTOC). An in silico analysis of transcription factor binding sites in plausible promoter regions of differentially expressed genes suggests that STAT1 is involved in TRAF6- and NIK-dependent gene expression. Indeed, the signal of RANK, a TNF receptor family member that activates TRAF6 and NIK, induces the activation of STAT1 in 2DG-FTOC. Moreover, RANK signaling induces the up-regulation of interferon (IFN)-stimulated gene (ISG) expression, suggesting that the RANKL-dependent activation of STAT1 up-regulates ISG expression. The RANKL-dependent expression levels of ISGs were reduced but not completely abolished in interferon α receptor 1-deficient (Ifnar1(-/-)) 2DG-FTOC. Our data suggest that RANK signaling induces ISG expression in both type I interferon-independent and interferon-dependent mechanisms.
Asunto(s)
Células Epiteliales/inmunología , Regulación de la Expresión Génica , Interferón Tipo I/inmunología , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Autotolerancia/genética , Timo/inmunología , Animales , Feto , Ratones , Análisis de Secuencia por Matrices de Oligonucleótidos , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor de Interferón alfa y beta/genética , Transducción de Señal , Células del Estroma/inmunología , Factor 6 Asociado a Receptor de TNF/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
RANKL (receptor activator of NF-κB ligand) is a member of TNF (tumor-necrosis factor) family cytokine. Several genetic studies indicated critical roles of RANKL and its receptor RANK in bone homeostasis. RANKL-RANK signal regulates differentiation, survival and activation of osteoclasts. Therefore, suppression of the RANKL signal would be a promising strategy for interventions in osteoporosis or rheumatoid arthritis. Indeed, humanized anti-RANKL neutralizing antibody is coming onto the market as an antiresorptive agent for osteoporosis treatment. In addition to the role on bone homeostasis, several studies suggested that the RANKL-RANK interaction regulates immune response and development. For instance, RANKL was previously identified as a survival factor for dendritic cells. Moreover, we and other groups reported that the RANKL signal contributes to development of medullary thymic epithelial cells (mTECs) . mTECs ectopically express and present a number of tissue restricted antigens (e.g. insulin) of which expressions are in part regulated by autoimmune regulator (Aire) , a factor responsible for a genetic human autoimmune disorder, thereby eliminating T cells reactive to these tissue restricted self-antigens. As result, RANKL is involved in establishment of self-tolerance in thymus by regulating the development of mTECs expressing Aire and tissue restricted antigens.
Asunto(s)
Autoinmunidad/genética , Diferenciación Celular/genética , Células Epiteliales/citología , Células Epiteliales/inmunología , Tolerancia Inmunológica/genética , Ligando RANK/fisiología , Transducción de Señal/fisiología , Timo/citología , Humanos , Timo/inmunologíaRESUMEN
While CD69 may regulate thymocyte egress by inhibiting S1P1 expression, CD69 expression is not thought to be required for normal thymocyte development. Here we show that CD69 is in fact specifically required for the differentiation of mature NKT2 cells, which do not themselves express CD69. Mechanistically, CD69 expression is required on CD24+ PLZFhi innate precursors for their retention in the thymus and completion of their differentiation into mature NKT2 cells. By contrast, CD69-deficient CD24+ PLZFhi innate precursors express S1P1 and prematurely exit the thymus, while S1P1 inhibitor treatment of CD69-deficient mice retains CD24+ PLZFhi innate precursors in the thymus and restores NKT2 cell differentiation. Thus, CD69 prevents S1P1 expression on CD24+ PLZFhi innate precursor cells from aborting NKT2 differentiation in the thymus. This study reveals the importance of CD69 to prolong the thymic residency time of developing immature precursors for proper differentiation of a T cell subset.
Asunto(s)
Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Lectinas Tipo C/genética , Linfopoyesis/genética , Células T Asesinas Naturales/citología , Receptores de Lisoesfingolípidos/genética , Subgrupos de Linfocitos T/citología , Timocitos/citología , Animales , Antígeno CD24/metabolismo , Diferenciación Celular , Regulación de la Expresión Génica , Ratones , Ratones Noqueados , Células T Asesinas Naturales/metabolismo , Proteína de la Leucemia Promielocítica con Dedos de Zinc/metabolismo , Receptores de Esfingosina-1-Fosfato , Subgrupos de Linfocitos T/metabolismo , Timocitos/metabolismoRESUMEN
Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire(+) mTECs) is unclear. Here, we describe novel embryonic precursors of Aire(+) mTECs. We found the candidate precursors of Aire(+) mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire(+) mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire(+) mTECs and efficiently suppressed the onset of autoimmunity induced by Aire(+) mTEC deficiency. Mechanistically, pMECs differentiated into Aire(+) mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-ß receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire(+) mTECs.
Asunto(s)
Diferenciación Celular/inmunología , Células Epiteliales/inmunología , Regulación de la Expresión Génica/inmunología , Células Madre Embrionarias de Ratones/inmunología , Timo/inmunología , Factores de Transcripción/inmunología , Animales , Diferenciación Celular/genética , Células Epiteliales/citología , Regulación de la Expresión Génica/genética , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Células Madre Embrionarias de Ratones/citología , Lectinas de Plantas/genética , Lectinas de Plantas/inmunología , Timo/citología , Factores de Transcripción/genética , Proteína AIRERESUMEN
Nuclear factor (NF)-κB-inducing kinase (NIK) is a serine/threonine kinase that activates NF-κB pathways, thereby regulating a wide variety of immune systems. Aberrant NIK activation causes tumor malignancy, suggesting a requirement for precise regulation of NIK activity. To explore novel interacting proteins of NIK, we performed in vitro virus screening and identified the catalytic subunit Aα isoform of serine/threonine phosphatase calcineurin (CnAα) as a novel NIK-interacting protein. The interaction of NIK with CnAα in living cells was confirmed by co-immunoprecipitation. Calcineurin catalytic subunit Aß isoform (CnAß) also bound to NIK. Experiments using domain deletion mutants suggested that CnAα and CnAß interact with both the kinase domain and C-terminal region of NIK. Moreover, the phosphatase domain of CnAα is responsible for the interaction with NIK. Intriguingly, we found that TRAF3, a critical regulator of NIK activity, also binds to CnAα and CnAß. Depletion of CnAα and CnAß significantly enhanced lymphotoxin-ß receptor (LtßR)-mediated expression of the NIK-dependent gene Spi-B and activation of RelA and RelB, suggesting that CnAα and CnAß attenuate NF-κB activation mediated by LtßR-NIK signaling. Overall, these findings suggest a possible role of CnAα and CnAß in modifying NIK functions.
Asunto(s)
Calcineurina/metabolismo , Regulación de la Expresión Génica , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Dominio Catalítico , Línea Celular/metabolismo , Citocina TWEAK , Humanos , Isoenzimas , Receptor beta de Linfotoxina/metabolismo , Ratones , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-ets/genética , Transducción de Señal , Factor 3 Asociado a Receptor de TNF/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Transcripción ReIB/metabolismo , Factores de Transcripción/genética , Factores de Necrosis Tumoral/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
T cell receptor (TCR)-mediated inhibition of interleukin-7 (IL-7) signaling is important for lineage fate determination in the thymus and for T cell survival in the periphery because uninterrupted IL-7 signaling results in T cell death. The initial event in IL-7 signaling is the transactivation of Janus kinases 1 and 3 (Jak1 and Jak3), which are associated with the cytosolic tails of the IL-7 receptor α chain (IL-7Rα) and the γc subunit, the two cell surface proteins that constitute IL-7R. We found that Jak1 is a highly unstable protein with a half-life of only 1.5 hours, so that continuous Jak1 protein synthesis is required to maintain Jak1 protein in sufficient abundance to support IL-7 signaling. However, we also found that Jak1 protein synthesis was acutely reduced by TCR-responsive microRNAs in the miR-17 family, which targeted Jak1 mRNA (messenger RNA) to inhibit its translation. Thus, this study identifies a molecular mechanism by which TCR engagement acutely disrupts IL-7 signaling.
Asunto(s)
Regulación de la Expresión Génica/inmunología , Janus Quinasa 1/genética , MicroARNs/metabolismo , ARN Mensajero/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Interleucina-7/metabolismo , Transducción de Señal/inmunología , Animales , Western Blotting , Citometría de Flujo , Inmunoprecipitación , Janus Quinasa 1/biosíntesis , Luciferasas , Ratones , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-7/antagonistas & inhibidoresRESUMEN
Virus-derived double-stranded RNAs (dsRNAs) are sensed in the cytosol by retinoic acid-inducible gene (RIG)-I-like receptors (RLRs). These induce the expression of type I IFN and proinflammatory cytokines through signaling pathways mediated by the mitochondrial antiviral signaling (MAVS) protein. TNF receptor-associated factor (TRAF) family proteins are reported to facilitate the RLR-dependent expression of type I IFN by interacting with MAVS. However, the precise regulatory mechanisms remain unclear. Here, we show the role of FK506-binding protein 51 (FKBP51) in regulating the dsRNA-dependent expression of type I IFN. The binding of FKBP51 to TRAF6 was first identified by "in vitro virus" selection and was subsequently confirmed with a coimmunoprecipitation assay in HEK293T cells. The TRAF-C domain of TRAF6 is required for its interaction, although FKBP51 does not contain the consensus motif for interaction with the TRAF-C domain. Besides TRAF6, we found that FKBP51 also interacts with TRAF3. The depletion of FKBP51 reduced the expression of type I IFN induced by dsRNA transfection or Newcastle disease virus infection in murine fibroblasts. Consistent with this, the FKBP51 depletion attenuated dsRNA-mediated phosphorylations of IRF3 and JNK and nuclear translocation of RelA. Interestingly, dsRNA stimulation promoted the accumulation of FKBP51 in the mitochondria. Moreover, the overexpression of FKBP51 inhibited RLR-dependent transcriptional activation, suggesting a scaffolding function for FKBP51 in the MAVS-mediated signaling pathway. Overall, we have demonstrated that FKBP51 interacts with TRAF proteins and facilitates the expression of type I IFN induced by cytosolic dsRNA. These findings suggest a novel role for FKBP51 in the innate immune response to viral infection.
Asunto(s)
Núcleo Celular/metabolismo , Regulación de la Expresión Génica , Interferón Tipo I/genética , Mitocondrias/metabolismo , Proteínas de Unión a Tacrolimus/metabolismo , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Animales , Línea Celular , Humanos , Inmunidad Innata , Interferón Tipo I/metabolismo , Ratones , Virus de la Enfermedad de Newcastle/genética , Virus de la Enfermedad de Newcastle/inmunología , Virus de la Enfermedad de Newcastle/metabolismo , Unión Proteica , Mapeo de Interacción de Proteínas , Mapas de Interacción de Proteínas , Transporte de Proteínas , ARN Bicatenario/metabolismo , Transducción de Señal , Factor 3 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/metabolismo , Proteínas de Unión a Tacrolimus/genéticaRESUMEN
Medullary thymic epithelial cells (mTECs) expressing the autoimmune regulator AIRE and various tissue-specific antigens (TSAs) are critical for preventing the onset of autoimmunity and may attenuate tumor immunity. However, molecular mechanisms controlling mTEC development remain elusive. Here, we describe the roles of the transcription factor Spi-B in mTEC development. Spi-B is rapidly up-regulated by receptor activator of NF-κB ligand (RANKL) cytokine signaling, which triggers mTEC differentiation, and in turn up-regulates CD80, CD86, some TSAs, and the natural inhibitor of RANKL signaling, osteoprotegerin (OPG). Spi-B-mediated OPG expression limits mTEC development in neonates but not in embryos, suggesting developmental stage-specific negative feedback regulation. OPG-mediated negative regulation attenuates cellularity of thymic regulatory T cells and tumor development in vivo. Hence, these data suggest that this negative RANKL-Spi-B-OPG feedback mechanism finely tunes mTEC development and function and may optimize the trade-off between prevention of autoimmunity and induction of antitumor immunity.
Asunto(s)
Células Epiteliales/inmunología , Tolerancia Inmunológica/inmunología , Proteínas Proto-Oncogénicas c-ets/inmunología , Timo/inmunología , Animales , Animales Recién Nacidos , Antígeno B7-1/inmunología , Antígeno B7-1/metabolismo , Western Blotting , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Células Epiteliales/metabolismo , Retroalimentación Fisiológica , Femenino , Expresión Génica/inmunología , Tolerancia Inmunológica/genética , Masculino , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Desnudos , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/inmunología , Osteoprotegerina/metabolismo , Proteínas Serina-Treonina Quinasas/inmunología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Proto-Oncogénicas c-ets/metabolismo , Ligando RANK/inmunología , Ligando RANK/metabolismo , Receptor Activador del Factor Nuclear kappa-B/genética , Receptor Activador del Factor Nuclear kappa-B/inmunología , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/inmunología , Timo/metabolismo , Quinasa de Factor Nuclear kappa BRESUMEN
Elimination of potential self-reactive T cells in the thymus is crucial for preventing the onset of autoimmune diseases. Epithelial cell subsets localized in thymic medulla [medullary thymic epithelial cells (mTECs)] contribute to this process by supplying a wide range of self-antigens that are otherwise expressed in a tissue-specific manner (TSAs). Expression of some TSAs in mTECs is controlled by the autoimmune regulator (AIRE) protein, of which dysfunctional mutations are the causative factor of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In addition to the elimination of self-reactive T cells, recent studies indicated roles of mTECs in the development of Foxp3-positive regulatory T cells, which suppress autoimmunity and excess immune reactions in peripheral tissues. The TNF family cytokines, RANK ligand, CD40 ligand, and lymphotoxin were found to promote the differentiation of AIRE- and TSA-expressing mTECs. Furthermore, activation of NF-κB is essential for mTEC differentiation. In this mini-review, we focus on molecular mechanisms that regulate induction of AIRE and TSA expression and discuss possible contributions of these mechanisms to prevent the onset of autoimmune diseases.
RESUMEN
Thymic epithelial cells (TECs) provide the microenvironment required for the development of T cells in the thymus. A unique property of medullary thymic epithelial cells (mTECs) is their expression of a wide range of tissue-restricted self-antigens, critically regulated by the nuclear protein AIRE, which contributes to the selection of the self-tolerant T cell repertoire, thereby suppressing the onset of autoimmune diseases. The TNF receptor family (TNFRF) protein receptor activator of NF-κB (RANK), CD40 and lymphotoxin ß receptor (LtßR) regulate the development and functions of mTECs. The engagement of these receptors with their specific ligands results in the activation of the NF-κB family of transcription factors. Two NF-κB activation pathways, the classical and non-classical pathways, promote the development of mature mTECs induced by these receptors. Consistently, TNF receptor-associated factor (TRAF6), the signal transducer of the classical pathway, and NF-κB inducing kinase (NIK), the signal transducer of the non-classical pathway, are essential for the development of mature mTECs. This review summarizes the current understanding of how the signaling by the TNF receptor family controls the development and functions of mTEC.
RESUMEN
The interaction between the receptor activator of NF-κB ligand (RANKL) and its receptor RANK plays a critical role in the development and function of diverse tissues. This review summarizes the studies regarding the functions of RANKL signaling in immune regulatory systems. Previous in vitro and in vivo studies have indicated that the RANKL signal promotes the survival of dendritic cells (DCs), thereby activating the immune response. In addition, RANKL signaling to DCs in the body surface barriers controls self-tolerance and oral-tolerance through regulatory T cell functions. In addition to regulating DC functions, the RANKL and RANK interaction is critical for the development and organization of several lymphoid organs. The RANKL signal initiates the formation of clusters of lymphoid tissue inducer cells, which is crucial for lymph node organogenesis. Moreover, the RANKL-RANK interaction controls the differentiation of M cells, specialized epithelial cells in mucosal tissues, that take up and transcytose antigen particles to control the immune response to pathogens or commensal bacterium. The development of epithelial cells localized in the thymic medulla (mTECs) is also regulated by the RANKL-RANK signal. Given that the unique property of mTECs to express a wide variety of tissue-specific self-antigens is critical for the elimination of self-antigen reactive T cells in the thymus, the RANKL-RANK interaction contributes to the suppression of autoimmunity. Future studies on the roles of the RANKL-RANK system in immune regulatory functions would be informative for the development and application of inhibitors of RANKL signaling for disease treatment.