RESUMO
The networks of transcription factors (TFs) that control intestinal-resident memory CD8+ T (TRM) cells, including multipotency and effector programs, are poorly understood. In this work, we investigated the role of the TF Bcl11b in TRM cells during infection with Listeria monocytogenes using mice with post-activation, conditional deletion of Bcl11b in CD8+ T cells. Conditional deletion of Bcl11b resulted in increased numbers of intestinal TRM cells and their precursors as well as decreased splenic effector and circulating memory cells and precursors. Loss of circulating memory cells was in part due to increased intestinal homing of Bcl11b-/- circulating precursors, with no major alterations in their programs. Bcl11b-/- TRM cells had altered transcriptional programs, with diminished expression of multipotent/multifunctional (MP/MF) program genes, including Tcf7, and up-regulation of the effector program genes, including Prdm1. Bcl11b also limits the expression of Ahr, another TF with a role in intestinal CD8+ TRM cell differentiation. Deregulation of TRM programs translated into a poor recall response despite TRM cell accumulation in the intestine. Reduced expression of MP/MF program genes in Bcl11b-/- TRM cells was linked to decreased chromatin accessibility and a reduction in activating histone marks at these loci. In contrast, the effector program genes displayed increased activating epigenetic status. These findings demonstrate that Bcl11b is a frontrunner in the tissue residency program of intestinal memory cells upstream of Tcf1 and Blimp1, promoting multipotency and restricting the effector program.
Assuntos
Linfócitos T CD8-Positivos , Fatores de Transcrição , Camundongos , Animais , Linfócitos T CD8-Positivos/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Diferenciação Celular , Intestinos , Proteínas Supressoras de Tumor/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismoRESUMO
Epigenetic landscapes can provide insight into regulation of gene expression and cellular diversity. Here, we examined the transcriptional and epigenetic profiles of seven human blood natural killer (NK) cell populations, including adaptive NK cells. The BCL11B gene, encoding a transcription factor (TF) essential for T cell development and function, was the most extensively regulated, with expression increasing throughout NK cell differentiation. Several Bcl11b-regulated genes associated with T cell signaling were specifically expressed in adaptive NK cell subsets. Regulatory networks revealed reciprocal regulation at distinct stages of NK cell differentiation, with Bcl11b repressing RUNX2 and ZBTB16 in canonical and adaptive NK cells, respectively. A critical role for Bcl11b in driving NK cell differentiation was corroborated in BCL11B-mutated patients and by ectopic Bcl11b expression. Moreover, Bcl11b was required for adaptive NK cell responses in a murine cytomegalovirus model, supporting expansion of these cells. Together, we define the TF regulatory circuitry of human NK cells and uncover a critical role for Bcl11b in promoting NK cell differentiation and function.
Assuntos
Diferenciação Celular/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Pré-Escolar , Montagem e Desmontagem da Cromatina , Elementos Facilitadores Genéticos , Epigênese Genética , Regulação da Expressão Gênica , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunofenotipagem , Lactente , Células Matadoras Naturais/citologia , Camundongos , Camundongos Knockout , Receptores KIR/genética , Receptores KIR/metabolismo , Proteínas Repressoras/genética , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Transcriptoma , Proteínas Supressoras de Tumor/genéticaRESUMO
During space missions, such as the prospective Mars mission, crew labor time is a strictly limited resource. The diet for such a mission (based on crops grown in a bioregenerative life support system) will require astronauts to prepare their meals essentially from raw ingredients. Time spent on food processing and preparation is time lost for other purposes. Recipe design and diet planning for a space mission should therefore incorporate the time required to prepare the recipes as a critical factor. In this study, videotape analysis of an experienced chef was used to develop a database of recipe preparation time. The measurements were highly consistent among different measurement teams. Data analysis revealed a wide variation between the active times of different recipes, underscoring the need for optimization of diet planning. Potential uses of the database developed in this study are discussed and illustrated in this work.
