Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
1.
Immunity ; 56(1): 207-223.e8, 2023 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-36580919

RESUMEN

Tissue-resident memory CD8+ T (TRM) cells are a subset of memory T cells that play a critical role in limiting early pathogen spread and controlling infection. TRM cells exhibit differences across tissues, but their potential heterogeneity among distinct anatomic compartments within the small intestine and colon has not been well recognized. Here, by analyzing TRM cells from the lamina propria and epithelial compartments of the small intestine and colon, we showed that intestinal TRM cells exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional, epigenetic, and functional heterogeneity. The T-box transcription factor Eomes, which represses TRM cell formation in some tissues, exhibited unexpected context-specific regulatory roles in supporting the maintenance of established TRM cells in the small intestine, but not in the colon. Taken together, these data provide previously unappreciated insights into the heterogeneity and differential requirements for the formation vs. maintenance of intestinal TRM cells.


Asunto(s)
Linfocitos T CD8-positivos , Células T de Memoria , Linfocitos T CD8-positivos/metabolismo , Memoria Inmunológica , Intestino Delgado , Colon
2.
J Immunol ; 200(12): 4012-4023, 2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29703862

RESUMEN

Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and ß subunits that mediate cell-to-cell and cell-to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a ß integrin-binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin α4ß1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function.


Asunto(s)
Integrinas/inmunología , Tolerancia Periférica/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/inmunología , Inflamación/inmunología , Ratones , Talina/inmunología , Transcriptoma/inmunología
3.
Plant Physiol ; 170(2): 989-99, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26662603

RESUMEN

Nitrogen is an essential soil nutrient for plants, and lack of nitrogen commonly limits plant growth. Soil nitrogen is typically available to plants in two inorganic forms: nitrate and ammonium. To better understand how nitrate and ammonium differentially affect plant metabolism and development, we performed transcriptional profiling of the shoots of ammonium-supplied and nitrate-supplied Arabidopsis (Arabidopsis thaliana) plants. Seven genes encoding class III glutaredoxins were found to be strongly and specifically induced by nitrate. RNA silencing of four of these glutaredoxin genes (AtGRXS3/4/5/8) resulted in plants with increased primary root length (approximately 25% longer than the wild type) and decreased sensitivity to nitrate-mediated inhibition of primary root growth. Increased primary root growth is also a well-characterized phenotype of many cytokinin-deficient plant lines. We determined that nitrate induction of glutaredoxin gene expression was dependent upon cytokinin signaling and that cytokinins could activate glutaredoxin gene expression independent of plant nitrate status. In addition, crosses between "long-root" cytokinin-deficient plants and "long-root" glutaredoxin-silenced plants generated hybrids that displayed no further increase in primary root length (i.e. epistasis). Collectively, these findings suggest that AtGRXS3/4/5/8 operate downstream of cytokinins in a signal transduction pathway that negatively regulates plant primary root growth in response to nitrate. This pathway could allow Arabidopsis to actively discriminate between different nitrogen sources in the soil, with the preferred nitrogen source, nitrate, acting to suppress primary root growth (vertical dimension) in concert with its well-characterized stimulatory effect on lateral root growth (horizontal dimension).


Asunto(s)
Arabidopsis/crecimiento & desarrollo , Arabidopsis/metabolismo , Glutarredoxinas/metabolismo , Nitratos/farmacología , Raíces de Plantas/crecimiento & desarrollo , Compuestos de Amonio/farmacología , Arabidopsis/efectos de los fármacos , Citocininas/metabolismo , Epistasis Genética/efectos de los fármacos , Silenciador del Gen/efectos de los fármacos , Raíces de Plantas/efectos de los fármacos , Raíces de Plantas/metabolismo , Brotes de la Planta/efectos de los fármacos , Brotes de la Planta/genética , Plantas Modificadas Genéticamente , Transducción de Señal/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Transcriptoma/genética , Regulación hacia Arriba/efectos de los fármacos
4.
Inflamm Bowel Dis ; 29(10): 1602-1612, 2023 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-37235748

RESUMEN

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease are 2 types of inflammatory bowel disease (IBD), a group of chronic digestive disorders caused by aberrant immune responses to intestinal microbes. Although changes in the composition of immune cell subsets in the context of IBD have been previously described, the interactions and communication among cells are less well understood. Moreover, the precise mechanisms of action underlying many biologic therapies, including the anti-α4ß7 integrin antagonist vedolizumab, remain incompletely understood. Our study aimed to explore possible additional mechanisms through which vedolizumab acts. METHODS: We performed cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on peripheral blood and colon immune cells derived from patients with ulcerative colitis treated with the anti-α4ß7 integrin antagonist vedolizumab. We applied a previously published computational approach, NicheNet, to predict immune cell-cell interactions, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications (CCC). RESULTS: We observed decreased proportions of T helper 17 (TH17) cells in UC patients who responded to vedolizumab and therefore focused the study on identifying cell-cell communications and signals of TH17 cells with other immune cells. For example, we observed that colon TH17 cells from vedolizumab nonresponders were predicted to have a greater degree of interactions with classical monocytes compared with responders, whereas colon TH17 cells from vedolizumab responders exhibited more interactions with myeloid dendritic cells compared with nonresponders. CONCLUSIONS: Overall, our results indicate that efforts to elucidate cell-cell communications among immune and nonimmune cell types may increase the mechanistic understanding of current and investigational therapies for IBD.


Compared to ulcerative patients unresponsive to vedolizumab, immune cell networks of ulcerative colitis patients responsive to vedolizumab have decreased proportion of TH17 and less pro-inflammatory signaling in the gut. Decreased pro-TH17 and interleukin (IL)-1 signaling from classical monocytes and innate immunocytes may mediate this phenotype.


Asunto(s)
Colitis Ulcerosa , Enfermedades Inflamatorias del Intestino , Humanos , Colitis Ulcerosa/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Integrinas , Comunicación Celular , Fármacos Gastrointestinales/uso terapéutico , Fármacos Gastrointestinales/farmacología
5.
Clin Transl Gastroenterol ; 14(5): e00576, 2023 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-36854061

RESUMEN

INTRODUCTION: Crohn's disease (CD) is a major subtype of inflammatory bowel disease (IBD), a spectrum of chronic intestinal disorders caused by dysregulated immune responses to gut microbiota. Although transcriptional and functional changes in a number of immune cell types have been implicated in the pathogenesis of IBD, the cellular interactions and signals that drive these changes have been less well-studied. METHODS: We performed Cellular Indexing of Transcriptomes and Epitopes by sequencing on peripheral blood, colon, and ileal immune cells derived from healthy subjects and patients with CD. We applied a previously published computational approach, NicheNet, to predict immune cell types interacting with CD8 + T-cell subsets, revealing putative ligand-receptor pairs and key transcriptional changes downstream of these cell-cell communications. RESULTS: As a number of recent studies have revealed a potential role for CD8 + T-cell subsets in the pathogenesis of IBD, we focused our analyses on identifying the interactions of CD8 + T-cell subsets with other immune cells in the intestinal tissue microenvironment. We identified ligands and signaling pathways that have implicated in IBD, such as interleukin-1ß, supporting the validity of the approach, along with unexpected ligands, such as granzyme B, which may play previously unappreciated roles in IBD. DISCUSSION: Overall, these findings suggest that future efforts focused on elucidating cell-cell communications among immune and nonimmune cell types may further our understanding of IBD pathogenesis.


Asunto(s)
Enfermedad de Crohn , Enfermedades Inflamatorias del Intestino , Humanos , Ligandos , Enfermedades Inflamatorias del Intestino/metabolismo , Linfocitos T CD8-positivos/metabolismo , Comunicación Celular
6.
Sci Immunol ; 5(47)2020 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-32414833

RESUMEN

During an immune response to microbial infection, CD8+ T cells give rise to distinct classes of cellular progeny that coordinately mediate clearance of the pathogen and provide long-lasting protection against reinfection, including a subset of noncirculating tissue-resident memory (TRM) cells that mediate potent protection within nonlymphoid tissues. Here, we used single-cell RNA sequencing to examine the gene expression patterns of individual CD8+ T cells in the spleen and small intestine intraepithelial lymphocyte (siIEL) compartment throughout the course of their differentiation in response to viral infection. These analyses revealed previously unknown transcriptional heterogeneity within the siIEL CD8+ T cell population at several stages of differentiation, representing functionally distinct TRM cell subsets and a subset of TRM cell precursors within the tissue early in infection. Together, these findings may inform strategies to optimize CD8+ T cell responses to protect against microbial infection and cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Animales , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Femenino , Células HEK293 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos
7.
Sci Immunol ; 5(50)2020 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-32826341

RESUMEN

Inflammatory bowel disease (IBD) encompasses a spectrum of gastrointestinal disorders driven by dysregulated immune responses against gut microbiota. We integrated single-cell RNA and antigen receptor sequencing to elucidate key components, cellular states, and clonal relationships of the peripheral and gastrointestinal mucosal immune systems in health and ulcerative colitis (UC). UC was associated with an increase in IgG1+ plasma cells in colonic tissue, increased colonic regulatory T cells characterized by elevated expression of the transcription factor ZEB2, and an enrichment of a γδ T cell subset in the peripheral blood. Moreover, we observed heterogeneity in CD8+ tissue-resident memory T (TRM) cells in colonic tissue, with four transcriptionally distinct states of differentiation observed across health and disease. In the setting of UC, there was a marked shift of clonally related CD8+ TRM cells toward an inflammatory state, mediated, in part, by increased expression of the T-box transcription factor Eomesodermin. Together, these results provide a detailed atlas of transcriptional changes occurring in adaptive immune cells in the context of UC and suggest a role for CD8+ TRM cells in IBD.


Asunto(s)
Colitis Ulcerosa/inmunología , Linfocitos Intraepiteliales/inmunología , Células T de Memoria/inmunología , Linfocitos T Reguladores/inmunología , Inmunidad Adaptativa , Animales , Colon/inmunología , Humanos , Inmunoglobulina G/inmunología , Masculino , Ratones Transgénicos , Análisis de la Célula Individual
8.
J Clin Invest ; 127(10): 3609-3623, 2017 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-28846070

RESUMEN

During an immune response, CD8+ T lymphocytes can undergo asymmetric division, giving rise to daughter cells that exhibit distinct tendencies to adopt terminal effector and memory cell fates. Here we show that "pre-effector" and "pre-memory" cells resulting from the first CD8+ T cell division in vivo exhibited low and high rates of endogenous proteasome activity, respectively. Pharmacologic reduction of proteasome activity in CD8+ T cells early during differentiation resulted in acquisition of terminal effector cell characteristics, whereas enhancement of proteasome activity conferred attributes of memory lymphocytes. Transcriptomic and proteomic analyses revealed that modulating proteasome activity in CD8+ T cells affected cellular metabolism. These metabolic changes were mediated, in part, through differential expression of Myc, a transcription factor that controls glycolysis and metabolic reprogramming. Taken together, these results demonstrate that proteasome activity is an important regulator of CD8+ T cell fate and raise the possibility that increasing proteasome activity may be a useful therapeutic strategy to enhance the generation of memory lymphocytes.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , División Celular/inmunología , Glucólisis/inmunología , Memoria Inmunológica , Complejo de la Endopetidasa Proteasomal/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Ratones , Ratones Mutantes , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas c-myc/inmunología , Proteínas Proto-Oncogénicas c-myc/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA