RESUMEN
The high affinity interleukin (IL)-15 receptor, IL-15Ralpha, is essential for supporting lymphoid homeostasis. To assess whether IL-15Ralpha's role in vivo is to trans present IL-15, we generated mixed bone marrow chimera from IL-15Ralpha- and IL-2/15Rbeta-deficient mice. We find that IL-15Ralpha-competent, IL-2/15Rbeta-deficient cells are able to support IL-15Ralpha-deficient natural killer (NK) and memory CD8+ T cells, thus ruling out secondary signals on these cells and demonstrating that IL-15Ralpha-mediated presentation of IL-15 in trans is the primary mechanism by which IL-15Ralpha functions in vivo. Surprisingly, using IL-15- and IL-15Ralpha-deficient mixed chimera, we also find that IL-15 and IL-15Ralpha must be expressed by the same cells to present IL-15 in trans, indicating that IL-15Ralpha is required on a cellular level for the elaboration of IL-15. These studies indicate that IL-15Ralpha defines homeostatic niches for NK and memory CD8+ T cells by controlling both the production and the presentation of IL-15 in trans to NK and CD8+ memory T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Homeostasis/inmunología , Interleucina-15/metabolismo , Células Asesinas Naturales/inmunología , Receptores de Interleucina-2/metabolismo , Animales , Células de la Médula Ósea , Citometría de Flujo , Memoria Inmunológica/inmunología , Interleucina-15/inmunología , Ratones , Ratones Endogámicos C57BL , Modelos Inmunológicos , Quimera por Radiación , Receptores de Interleucina-15 , Receptores de Interleucina-2/inmunologíaRESUMEN
Natural killer (NK) cells protect hosts against viral pathogens and transformed cells. IL-15 is thought to play a critical role in NK cell development, but its role in the regulation of peripheral NK cells is less well defined. We now find that adoptive transfer of normal NK cells into mice lacking the high affinity interleukin (IL)-15 receptor, IL-15Ralpha, surprisingly results in the abrupt loss of these cells. Moreover, IL-15Ralpha-deficient NK cells can differentiate successfully in radiation bone marrow chimera bearing normal cells. Finally, adoptively transferred IL-15Ralpha-deficient NK cells survive in normal but not IL-15Ralpha-deficient mice. These findings demonstrate that NK cell-independent IL-15Ralpha expression is critical for maintaining peripheral NK cells, while IL-15Ralpha expression on NK cells is not required for this function.
Asunto(s)
Supervivencia Celular/fisiología , Células Asesinas Naturales/metabolismo , Receptores de Interleucina-2/metabolismo , Traslado Adoptivo , Animales , Homeostasis , Interleucina-15/genética , Interleucina-15/metabolismo , Células Asesinas Naturales/citología , Ratones , Ratones Endogámicos , Ratones Noqueados , Quimera por Radiación/fisiología , Receptores de Interleucina-15 , Receptores de Interleucina-2/genética , Transducción de Señal/fisiología , Bazo/citologíaRESUMEN
Pluripotent bone marrow-derived side population (BM-SP) stem cells have been shown to repopulate the hematopoietic system and to contribute to skeletal and cardiac muscle regeneration after transplantation. We tested BM-SP cells for their ability to regenerate heart and skeletal muscle using a model of cardiomyopathy and muscular dystrophy that lacks delta-sarcoglycan. The absence of delta-sarcoglycan produces microinfarcts in heart and skeletal muscle that should recruit regenerative stem cells. Additionally, sarcoglycan expression after transplantation should mark successful stem cell maturation into cardiac and skeletal muscle lineages. BM-SP cells from normal male mice were transplanted into female delta-sarcoglycan-null mice. We detected engraftment of donor-derived stem cells into skeletal muscle, with the majority of donor-derived cells incorporated within myofibers. In the heart, donor-derived nuclei were detected inside cardiomyocytes. Skeletal muscle myofibers containing donor-derived nuclei generally failed to express sarcoglycan, with only 2 sarcoglycan-positive fibers detected in the quadriceps muscle from all 14 mice analyzed. Moreover, all cardiomyocytes with donor-derived nuclei were sarcoglycan-negative. The absence of sarcoglycan expression in cardiomyocytes and skeletal myofibers after transplantation indicates impaired differentiation and/or maturation of bone marrow-derived stem cells. The inability of BM-SP cells to express this protein severely limits their utility for cardiac and skeletal muscle regeneration.
Asunto(s)
Corazón/fisiología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/fisiología , Músculo Esquelético/fisiología , Miocardio/metabolismo , Células Madre Pluripotentes/fisiología , Sarcoglicanos/metabolismo , Animales , Biomarcadores , Núcleo Celular/metabolismo , Separación Celular , Femenino , Corazón/anatomía & histología , Células Madre Hematopoyéticas/citología , Hibridación Fluorescente in Situ , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Esquelético/citología , Músculo Esquelético/patología , Músculo Esquelético/efectos de la radiación , Miocardio/citología , Miocardio/patología , Miocitos Cardíacos/citología , Miocitos Cardíacos/metabolismo , Células Madre Pluripotentes/citología , Sarcoglicanos/genética , Cromosoma YRESUMEN
Interleukin-15 (IL-15) is a cytokine that plays unique roles in both innate and adaptive immune cell homeostasis. While early studies suggested that IL-15 resembled IL-2, more recent work suggests that IL-15 may play multiple unique roles in immune homeostasis befitting its pleiotropic expression pattern. This review will focus on recent studies that highlight some of these functions.
Asunto(s)
Interleucina-15/fisiología , Linfocitos/inmunología , Animales , Homeostasis , Memoria Inmunológica , Interleucina-2/fisiología , Activación de Linfocitos , Receptores de Interleucina-15 , Receptores de Interleucina-2/metabolismo , Transducción de Señal , Linfocitos T/inmunologíaRESUMEN
The intestinal lamina propria contains lymphocytes that are chronically activated by exposure to luminal antigens. Dysregulation of these cells is thought to be central to the pathogenesis of bowel inflammation in experimental models of inflammatory bowel disease. CD28 signals on peripheral T cells provide important costimulatory signals that enhance T-cell proliferation and activation responses to antigens. However, the role of CD28 signals in lamina propria T cells or models of inflammatory bowel disease have not been determined. Accordingly, we examined T lymphocyte activation and proliferation in CD28-deficient (CD28-/-) mice to examine the in vivo roles of CD28 signals in lamina propria T-cell homeostasis. We further generated CD28-/- interleukin (IL)-2-/- double mutant mice to assess the role of CD28 signals in supporting the spontaneously activated and pathogenic T cells that accumulate in IL-2-/- mice. CD28-/- lamina propria T cells displayed reduced activation markers, but were present in normal numbers and proliferated normally. IL-2-/- lymphocytes expressed high levels of bcl-xL, whereas CD28-/- IL-2-/- cells had substantially less bcl-xL. However, lymphadenopathy and ulcerative colitis-like disease occurred in both IL-2-/- and CD28-/- IL-2-/- mice. Thus, CD28 provides a functional costimulatory signal to lamina propria T cells but is not required for homeostasis of these cells. In addition, neither CD28 nor bcl-xL appears to be required for the spontaneous accumulation of T cells in IL-2-/- mice. This suggests that other costimulatory molecules or T-cell receptor ligation alone drive lymphocyte expansion in IL-2-deficient mice.
Asunto(s)
Antígenos CD28/genética , Antígenos CD28/fisiología , Colitis/genética , Colitis/fisiopatología , Interleucina-2/deficiencia , Interleucina-2/fisiología , Activación de Linfocitos/genética , Activación de Linfocitos/fisiología , Animales , Modelos Animales de Enfermedad , Interleucina-2/genética , Mucosa Intestinal/fisiopatología , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/genética , Transducción de Señal/fisiología , Linfocitos T/fisiologíaAsunto(s)
FN-kappa B/fisiología , Comunicación Celular , Proteínas de Unión al ADN , Humanos , Interleucina-1/fisiología , Péptidos y Proteínas de Señalización Intracelular , Lipopolisacáridos/farmacología , Proteínas de Microtúbulos/fisiología , Proteínas Nucleares , Proteínas/fisiología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa , Factor de Necrosis Tumoral alfa/fisiología , Dedos de Zinc/fisiologíaRESUMEN
NK cells protect hosts against viral pathogens and transformed cells, and dendritic cells (DCs) play important roles in activating NK cells. We now find that murine IL-15Ralpha-deficient DCs fail to support NK cell cytolytic activity and elaboration of IFN-gamma, despite the fact that these DCs express normal levels of costimulatory molecules and IL-12. By contrast, IL-15Ralpha expression on NK cells is entirely dispensable for their activation by DCs. In addition, blockade with anti-IL-15Ralpha and anti-IL-2Rbeta but not anti-IL-2Ralpha-specific Abs prevents NK cell activation by wild-type DCs. Finally, presentation of IL-15 by purified IL-15Ralpha/Fc in trans synergizes with IL-12 to support NK cell priming. These findings suggest that murine DCs require IL-15Ralpha to present IL-15 in trans to NK cells during NK cell priming.
Asunto(s)
Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Subunidades de Proteína/fisiología , Receptores de Interleucina-2/fisiología , Animales , Anticuerpos Bloqueadores/farmacología , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Sistema Libre de Células/inmunología , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/citología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Inmunosupresores/farmacología , Interleucina-15/metabolismo , Interleucina-15/fisiología , Activación de Linfocitos/genética , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Subunidades de Proteína/antagonistas & inhibidores , Subunidades de Proteína/inmunología , Subunidades de Proteína/metabolismo , Receptores de Interleucina-15 , Receptores de Interleucina-2/antagonistas & inhibidores , Receptores de Interleucina-2/inmunología , Receptores de Interleucina-2/metabolismoRESUMEN
IL-2 receptor alpha-deficient (IL2Ralpha-/-) mice spontaneously accumulate vast numbers of intestinal lamina propria (LP) T cells and develop bowel inflammation. The accumulation of T cells in IL2Ralpha-/- mice is thought to result, in part, from defective Fas-induced cell death. To understand the role of cell proliferation and death in regulating LP T cells in IL2Ralpha-/- mice, we have directly examined the proliferation and Fas sensitivity of wild-type, lpr/lpr, and IL2Ralpha-/- LP T cells. In wild-type mice, 5'-bromodeoxyuridine (BrdU) labeling and Fas susceptibility are greatest in CD44Hi LP T cells. Fas-deficient lpr/lpr mice have normal total numbers of LP T cells, despite an increased proportion of BrdU+ T cells. By contrast, IL2Ralpha-/- mice possess increased total numbers of LP T cells, despite normal proportions of BrdU+ LP T cells. Finally, wild-type and IL2Ralpha-/- LP T cells are equivalently Fas sensitive. These results demonstrate that LP T cells proliferate and are Fas-sensitive cells. IL2Ralpha-/- mice accumulate a large number of these Fas-sensitive LP T cells and clearly differ from Fas-deficient lpr/lpr mice in this regard. Thus our studies reveal that Fas is dispensable for LP T cell homeostasis and suggest that the intestinal inflammation observed in IL2Ralpha-/- mice is independent of defective Fas-induced cell death.
Asunto(s)
Intestinos/patología , Linfocitos T/fisiología , Receptor fas/fisiología , Animales , Apoptosis , Bromodesoxiuridina/metabolismo , División Celular , Homeostasis , Receptores de Hialuranos/análisis , Hipertrofia , Enfermedades Inflamatorias del Intestino/etiología , Enfermedades Inflamatorias del Intestino/patología , Mucosa Intestinal/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-2/deficiencia , Receptores de Interleucina-2/fisiología , Linfocitos T/inmunología , Linfocitos T/patología , Timectomía , Receptor fas/genéticaRESUMEN
The generation and maintenance of immunological memory requires the activation, expansion, and persistent proliferation of antigen-specific T cells. Recent work suggests that IL-15 may be important for this process. Surprisingly, we now find that expression of the high-affinity receptor for IL-15, IL-15R alpha, on T cells is dispensable for the generation or maintenance of memory CD8(+) T cells. By contrast, IL-15R alpha expression on cells other than T cells is absolutely critical for this function. These findings may be related to IL-15R alpha's ability to present IL-15 in trans to low-affinity IL-15R beta gamma(c) receptors on memory CD8(+) T cells. These unexpected results provide insights into how IL-15R alpha supports memory CD8(+) T cells.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Receptores de Interleucina-2/metabolismo , Adyuvantes Inmunológicos/farmacología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/efectos de los fármacos , División Celular , Ratones , Ratones Congénicos , Ratones Endogámicos C57BL , Ratones Noqueados , Poli I-C/farmacología , Quimera por Radiación , Tolerancia a Radiación/inmunología , Receptores de Interleucina-15 , Receptores de Interleucina-2/deficiencia , Receptores de Interleucina-2/genética , Transducción de SeñalRESUMEN
A20 is a cytoplasmic protein required for the termination of tumor necrosis factor (TNF)-induced signals. We show here that mice doubly deficient in either A20 and TNF or A20 and TNF receptor 1 developed spontaneous inflammation, indicating that A20 is also critical for the regulation of TNF-independent signals in vivo. A20 was required for the termination of Toll-like receptor-induced activity of the transcription factor NF-kappaB and proinflammatory gene expression in macrophages, and this function protected mice from endotoxic shock. A20 accomplished this biochemically by directly removing ubiquitin moieties from the signaling molecule TRAF6. The critical function of this deubiquitinating enzyme in the restriction of TLR signals emphasizes the importance of the regulation of ubiquitin conjugation in innate immune cells.