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1.
Nat Immunol ; 16(6): 635-41, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25939026

RESUMEN

The thymic production of regulatory T cells (Treg cells) requires interleukin 2 (IL-2) and agonist T cell antigen receptor (TCR) ligands and is controlled by competition for a limited developmental niche, but the thymic sources of IL-2 and the factors that limit access to the niche are poorly understood. Here we found that IL-2 produced by antigen-bearing dendritic cells (DCs) had a key role in Treg cell development and that existing Treg cells limited new development of Treg cells by competing for IL-2. Our data suggest that antigen-presenting cells (APCs) that can provide both IL-2 and a TCR ligand constitute the thymic niche and that competition by existing Treg cells for a limited supply of IL-2 provides negative feedback for new production of Treg cells.


Asunto(s)
Células Dendríticas/fisiología , Interleucina-2/inmunología , Receptores de Antígenos de Linfocitos T/agonistas , Linfocitos T Reguladores/fisiología , Timo/inmunología , Animales , Presentación de Antígeno , Antígenos/inmunología , Diferenciación Celular , Línea Celular , Microambiente Celular , Retroalimentación Fisiológica , Interleucina-2/genética , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
2.
Immunity ; 45(1): 159-71, 2016 07 19.
Artículo en Inglés | MEDLINE | ID: mdl-27421704

RESUMEN

Highly functional CD8(+) effector T (Teff) cells can persist in large numbers during controlled persistent infections, as exemplified by rare HIV-infected individuals who control the virus. Here we examined the cellular mechanisms that maintain ongoing T effector responses using a mouse model for persistent Toxoplasma gondii infection. In mice expressing the protective MHC-I molecule, H-2L(d), a dominant T effector response against a single parasite antigen was maintained without a contraction phase, correlating with ongoing presentation of the dominant antigen. Large numbers of short-lived Teff cells were continuously produced via a proliferative, antigen-dependent intermediate (Tint) population with a memory-effector hybrid phenotype. During an acute, resolved infection, decreasing antigen load correlated with a sharp drop in the Tint cell population and subsequent loss of the ongoing effector response. Vaccination approaches aimed at the development of Tint populations might prove effective against pathogens that lead to chronic infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular , Subgrupos Linfocitarios/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Presentación de Antígeno , Antígenos de Protozoos/inmunología , Antígenos de Protozoos/metabolismo , Linfocitos T CD8-positivos/parasitología , Proliferación Celular , Células Cultivadas , Enfermedad Crónica , Citotoxicidad Inmunológica , Antígenos de Histocompatibilidad Clase I/metabolismo , Epítopos Inmunodominantes/inmunología , Epítopos Inmunodominantes/metabolismo , Memoria Inmunológica , Subgrupos Linfocitarios/parasitología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genética
3.
Immunity ; 29(3): 487-96, 2008 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-18718768

RESUMEN

Although the signals that control neutrophil migration from the blood to sites of infection have been well characterized, little is known about their migration patterns within lymph nodes or the strategies that neutrophils use to find their local sites of action. To address these questions, we used two-photon scanning-laser microscopy to examine neutrophil migration in intact lymph nodes during infection with an intracellular parasite, Toxoplasma gondii. We found that neutrophils formed both small, transient and large, persistent swarms via a coordinated migration pattern. We provided evidence that cooperative action of neutrophils and parasite egress from host cells could trigger swarm formation. Neutrophil swarm formation coincided in space and time with the removal of macrophages that line the subcapsular sinus of the lymph node. Our data provide insights into the cellular mechanisms underlying neutrophil swarming and suggest new roles for neutrophils in shaping immune responses.


Asunto(s)
Ganglios Linfáticos/inmunología , Macrófagos/inmunología , Neutrófilos/inmunología , Toxoplasma/inmunología , Toxoplasmosis Animal/inmunología , Animales , Movimiento Celular , Ganglios Linfáticos/citología , Ganglios Linfáticos/parasitología , Macrófagos/citología , Macrófagos/parasitología , Ratones , Neutrófilos/citología , Neutrófilos/parasitología
4.
Proc Natl Acad Sci U S A ; 110(21): E1913-22, 2013 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-23650399

RESUMEN

Toxoplasma gondii infection occurs through the oral route, but we lack important information about how the parasite interacts with the host immune system in the intestine. We used two-photon laser-scanning microscopy in conjunction with a mouse model of oral T. gondii infection to address this issue. T. gondii established discrete foci of infection in the small intestine, eliciting the recruitment and transepithelial migration of neutrophils and inflammatory monocytes. Neutrophils accounted for a high proportion of actively invaded cells, and we provide evidence for a role for transmigrating neutrophils and other immune cells in the spread of T. gondii infection through the lumen of the intestine. Our data identify neutrophils as motile reservoirs of T. gondii infection and suggest a surprising retrograde pathway for parasite spread in the intestine.


Asunto(s)
Movimiento Celular/inmunología , Intestino Delgado/inmunología , Infiltración Neutrófila/inmunología , Neutrófilos/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Modelos Animales de Enfermedad , Inmunidad Innata , Mucosa Intestinal/inmunología , Mucosa Intestinal/parasitología , Mucosa Intestinal/patología , Intestino Delgado/parasitología , Intestino Delgado/patología , Ratones , Ratones Transgénicos , Microscopía Confocal , Neutrófilos/parasitología , Neutrófilos/patología , Toxoplasmosis/parasitología , Toxoplasmosis/patología
5.
Immunol Cell Biol ; 92(10): 872-81, 2014 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-25155465

RESUMEN

The classic anti-viral cytokine interferon (IFN)-ß can be induced during parasitic infection, but relatively little is know about the cell types and signaling pathways involved. Here we show that inflammatory monocytes (IMs), but not neutrophils, produce IFN-ß in response to T. gondii infection. This difference correlated with the mode of parasite entry into host cells, with phagocytic uptake predominating in IMs and active invasion predominating in neutrophils. We also show that expression of IFN-ß requires phagocytic uptake of the parasite by IMs, and signaling through Toll-like receptors (TLRs) and MyD88. Finally, we show that IMs are major producers of IFN-ß in mesenteric lymph nodes following in vivo oral infection of mice, and mice lacking the receptor for type I IFN-1 show higher parasite loads and reduced survival. Our data reveal a TLR and internalization-dependent pathway in IMs for IFN-ß induction to a non-viral pathogen.


Asunto(s)
Interferón beta/biosíntesis , Monocitos/inmunología , Receptores Toll-Like/metabolismo , Toxoplasmosis Animal/inmunología , Animales , Inmunidad Innata , Ratones , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/metabolismo , Neutrófilos/inmunología , Transducción de Señal , Toxoplasma/inmunología , Toxoplasmosis Animal/parasitología
6.
Front Immunol ; 14: 1250316, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38022509

RESUMEN

MHC-E restricted CD8 T cells show promise in vaccine settings, but their development and specificity remain poorly understood. Here we focus on a CD8 T cell population reactive to a self-peptide (FL9) bound to mouse MHC-E (Qa-1b) that is presented in response to loss of the MHC I processing enzyme ERAAP, termed QFL T cells. We find that mature QFL thymocytes are predominantly CD8αß+CD4-, show signs of agonist selection, and give rise to both CD8αα and CD8αß intraepithelial lymphocytes (IEL), as well as memory phenotype CD8αß T cells. QFL T cells require the MHC I subunit ß-2 microglobulin (ß2m), but do not require Qa1b or classical MHC I for positive selection. However, QFL thymocytes do require Qa1b for agonist selection and full functionality. Our data highlight the relaxed requirements for positive selection of an MHC-E restricted T cell population and suggest a CD8αß+CD4- pathway for development of CD8αα IELs.


Asunto(s)
Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T alfa-beta , Animales , Ratones , Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Timocitos/metabolismo , Genes MHC Clase II
7.
Cell Rep ; 38(3): 110266, 2022 01 18.
Artículo en Inglés | MEDLINE | ID: mdl-35045305

RESUMEN

Production of effector CD8+ T cells during persistent infection requires a stable pool of stem-like cells that can give rise to effector cells via a proliferative intermediate population. In infection models marked by T cell exhaustion, this process can be transiently induced by checkpoint blockade but occurs spontaneously in mice chronically infected with the protozoan intracellular parasite Toxoplasma gondii. We observe distinct locations for parasite-specific T cell subsets, implying a link between differentiation and anatomical niches in the spleen. Loss of the chemokine receptor CXCR3 on T cells does not prevent white pulp-to-red pulp migration but reduces interactions with CXCR3 ligand-producing dendritic cells (DCs) and impairs memory-to-intermediate transition, leading to a buildup of memory T cells in the red pulp. Thus, CXCR3 increases T cell exposure to differentiation-inducing signals during red pulp migration, providing a dynamic mechanism for modulating effector differentiation in response to environmental signals.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Células Dendríticas/inmunología , Células Progenitoras Linfoides/inmunología , Receptores CXCR3/inmunología , Bazo/inmunología , Animales , Ratones , Infección Persistente/inmunología , Toxoplasmosis Animal/inmunología
8.
Mucosal Immunol ; 14(1): 68-79, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32483197

RESUMEN

Thymocytes bearing αß T cell receptors (TCRαß) with high affinity for self-peptide-MHC complexes undergo negative selection or are diverted to alternate T cell lineages, a process termed agonist selection. Among thymocytes bearing TCRs restricted to MHC class I, agonist selection can lead to the development of precursors that can home to the gut and give rise to CD8αα-expressing intraepithelial lymphocytes (CD8αα IELs). The factors that influence the choice between negative selection versus CD8αα IEL development remain largely unknown. Using a synchronized thymic tissue slice model that supports both negative selection and CD8αα IEL development, we show that the affinity threshold for CD8αα IEL development is higher than for negative selection. We also investigate the impact of peptide presenting cells and cytokines, and the migration patterns associated with these alternative cell fates. Our data highlight the roles of TCR affinity and the thymic microenvironments on T cell fate.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Selección Clonal Mediada por Antígenos , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Timo/inmunología , Timo/metabolismo , Linfocitos T CD8-positivos/citología , Microambiente Celular , Selección Clonal Mediada por Antígenos/genética , Selección Clonal Mediada por Antígenos/inmunología , Antígenos de Histocompatibilidad/química , Antígenos de Histocompatibilidad/genética , Antígenos de Histocompatibilidad/inmunología , Linfocitos Intraepiteliales/citología , Péptidos/inmunología , Timo/citología
9.
J Immunol ; 181(10): 7014-23, 2008 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-18981121

RESUMEN

Little is known about the dynamics of the interactions between thymocytes and other cell types, as well as the spatiotemporal distribution of thymocytes during positive selection in the microenvironment of the cortex. We used two-photon laser scanning microscopy of the mouse thymus to visualize thymocytes and dendritic cells (DCs) and to characterize their interactions in the cortex. We show that thymocytes make frequent contacts with DCs in the thymic cortex and that these associations increase when thymocytes express T cell receptors that mediate positive selection. We also show that cortical DCs and the chemokine CCL21 expression are closely associated with capillaries throughout the cortex. The overexpression of the chemokine receptor CCR7 in thymocytes results in an increase in DC-thymocyte interactions, while the loss of CCR7 in the background of a positive-selecting TCR reduces the extent of DC-thymocyte interactions. These observations identify a vasculature-associated microenvironment within the thymic cortex that promotes interactions between DCs and thymocytes that are receiving positive selection signals.


Asunto(s)
Comunicación Celular/inmunología , Células Dendríticas/inmunología , Receptores CCR7/metabolismo , Linfocitos T/inmunología , Timo/citología , Animales , Apoptosis/inmunología , Capilares/inmunología , Movimiento Celular/inmunología , Quimiocina CCL21/metabolismo , Células Dendríticas/citología , Técnica del Anticuerpo Fluorescente , Antígenos de Histocompatibilidad Clase I , Procesamiento de Imagen Asistido por Computador , Etiquetado Corte-Fin in Situ , Ratones , Ratones Transgénicos , Microscopía Confocal , Receptores de Antígenos de Linfocitos T/inmunología , Autotolerancia/inmunología , Linfocitos T/citología , Timo/irrigación sanguínea , Timo/inmunología
10.
Elife ; 82019 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-31868579

RESUMEN

Autoreactive thymocytes are eliminated during negative selection in the thymus, a process important for establishing self-tolerance. Thymic phagocytes serve to remove dead thymocytes, but whether they play additional roles during negative selection remains unclear. Here, using a murine thymic slice model in which thymocytes undergo negative selection in situ, we demonstrate that phagocytosis promotes negative selection, and provide evidence for the escape of autoreactive CD8 T cells to the periphery when phagocytosis in the thymus is impaired. We also show that negative selection is more efficient when the phagocyte also presents the negative selecting peptide. Our findings support a model for negative selection in which the death process initiated following strong TCR signaling is facilitated by phagocytosis. Thus, the phagocytic capability of cells that present self-peptides is a key determinant of thymocyte fate.


Asunto(s)
Muerte Celular , Activación de Linfocitos , Fagocitosis/fisiología , Timocitos/metabolismo , Animales , Presentación de Antígeno , Células de la Médula Ósea , Linfocitos T CD8-positivos/inmunología , Proteínas de Unión al ADN/genética , Proteínas de Homeodominio/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Péptidos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Autotolerancia , Transducción de Señal , Timo/inmunología
12.
Cell Rep ; 7(5): 1716-1728, 2014 Jun 12.
Artículo en Inglés | MEDLINE | ID: mdl-24857659

RESUMEN

CD8 T cells play a key role in defense against the intracellular parasite Toxoplasma, but why certain CD8 responses are more potent than others is not well understood. Here, we describe a parasite antigen, ROP5, that elicits a CD8 T cell response in genetically susceptible mice. ROP5 is secreted via parasite organelles termed rhoptries that are injected directly into host cells during invasion, whereas the protective, dense-granule antigen GRA6 is constitutively secreted into the parasitophorous vacuole. Transgenic parasites in which the ROP5 antigenic epitope was targeted for secretion through dense granules led to enhanced CD8 T cell responses, whereas targeting the GRA6 epitope to rhoptries led to reduced CD8 responses. CD8 T cell responses to the dense-granule-targeted ROP5 epitope resulted in reduced parasite load in the brain. These data suggest that the mode of secretion affects the efficacy of parasite-specific CD8 T cell responses.


Asunto(s)
Antígenos de Protozoos/inmunología , Linfocitos T CD8-positivos/inmunología , Proteínas Protozoarias/inmunología , Vías Secretoras , Toxoplasma/metabolismo , Secuencia de Aminoácidos , Animales , Antígenos de Protozoos/química , Epítopos/química , Epítopos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Datos de Secuencia Molecular , Proteínas Protozoarias/química , Toxoplasma/inmunología
13.
J Immunol ; 179(11): 7358-64, 2007 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-18025179

RESUMEN

During thymic development, T cell progenitors undergo positive selection based on the ability of their T cell Ag receptors (TCR) to bind MHC ligands on thymic epithelial cells. Positive selection determines T cell fate, in that thymocytes whose TCR bind MHC class I (MHC-I) develop as CD8-lineage T cells, whereas those that bind MHC class II (MHC-II) develop as CD4 T cells. Positive selection also induces migration from the cortex to the medulla driven by the chemokine receptor CCR7. In this study, we show that CCR7 is up-regulated in a larger proportion of CD4(+)CD8(+) thymocytes undergoing positive selection on MHC-I compared with MHC-II. Mice bearing a mutation of Th-POK, a key CD4/CD8-lineage regulator, display increased expression of CCR7 among MHC-II-specific CD4(+)CD8(+) thymocytes. In addition, overexpression of CCR7 results in increased development of CD8 T cells bearing MHC-II-specific TCR. These findings suggest that the timing of CCR7 expression relative to coreceptor down-regulation is regulated by lineage commitment signals.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Linaje de la Célula/inmunología , Receptores CCR7/biosíntesis , Timo/crecimiento & desarrollo , Timo/inmunología , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Ligandos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Unión Proteica , Receptores de Antígenos de Linfocitos T/inmunología , Receptores CCR7/inmunología , Timo/citología , Factores de Transcripción/inmunología , Regulación hacia Arriba/inmunología
14.
J Immunol ; 174(2): 890-7, 2005 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-15634911

RESUMEN

Both the Notch and TCR signaling pathways play an important role in T cell development, but the links between these signaling pathways are largely unexplored. The adapter protein Numb is a well-characterized inhibitor of Notch and also contains a phosphotyrosine binding domain, suggesting that Numb could provide a link between these pathways. We explored this possibility by investigating the physical interactions among Notch, Numb, and the TCR signaling apparatus and by examining the consequences of a Numb mutation on T cell development. We found that Notch and Numb cocluster with the TCR at the APC contact during Ag-driven T cell-APC interactions in both immature and mature T cells. Furthermore, Numb coimmunoprecipitates with components of the TCR signaling apparatus. Despite this association, T cell development and T cell activation occur normally in the absence of Numb, perhaps due to the expression of the related protein, Numblike. Together our data suggest that Notch and TCR signals may be integrated at the cell membrane, and that Numb may be an important adapter in this process.


Asunto(s)
Proteínas de la Membrana/fisiología , Proteínas del Tejido Nervioso/fisiología , Receptores de Antígenos de Linfocitos T/fisiología , Receptores de Superficie Celular/metabolismo , Transducción de Señal/inmunología , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Eliminación de Gen , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Receptor Notch1 , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Superficie Celular/fisiología , Transducción de Señal/genética , Linfocitos T/citología , Linfocitos T/inmunología , Timo/citología , Timo/metabolismo , Factores de Transcripción/fisiología
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