IL-2 and IL-15 drive intrathymic differentiation of functionally distinct regulatory T lymphocyte-clusters
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PROVIDER: PRJNA645186 | ENA |
REPOSITORIES: ENA
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Project description:Intrathymic development of Foxp3-expressing regulatory T lymphocytes (Treg) depends on signals from the TCR, cytokine-receptors, and other cell-surface receptors. The cytokines IL-2 and IL-15 have been suggested to quantitatively modulate Treg-development. However, recent evidence showed that very large proportions of thymic Treg are cells that had migrated from the periphery back to the thymus. It remained therefore unclear if IL-2 and IL-15 quantitatively control the development of Treg. Moreover, these cytokines may also contribute to the differentiation of functionally distinct Treg subsets. Using an experimental setting in which we unambiguously distinguish newly developing from recirculating Treg, we here address the quantitative and qualitative roles of IL-2 and IL-15 in Treg-development, selection, and differentiation. Our results definitively demonstrate that in absence of IL-2 or IL-15 the thymus produces substantially less Treg. Importantly, IL-2 and IL-15 drive the differentiation of transcriptionally and phenotypically distinct Treg clusters, the number of which is substantially higher than previously appreciated. These cytokines also differentially modulate the TCR-repertoire expressed by newly developing Treg. Adoptive transfer of Treg from wt, IL-2- or IL-15-deficient animals into Treg-deficient new-born Scurfy mice, revealed differences in the in vivo function of these cells. Combined, our results indicate that IL-2 and IL-15 drive the development of functionally complementary Treg clusters.
2025-07-05 | GSE154140 | GEO
Project description:Development of Foxp3-expressing regulatory T-lymphocytes (Treg) in the thymus is controlled by signals delivered in T-cell precursors via the TCR, co-stimulatory receptors, and cytokine receptors. In absence of IL-2, IL-15 or their receptors, fewer Treg apparently develop in the thymus. However, it was recently shown that a substantial part of thymic Treg are cells that had recirculated from the periphery back to the thymus, troubling interpretation of these results. We therefore reassessed the involvement of IL-2 and IL-15 in the development of Treg, taking into account Treg-recirculation. In three-week-old mice, when substantial amounts of recirculating Treg are present in the thymus, we found similarly reduced proportions of newly developed Treg in absence of IL-2 or IL-15, and in absence of both cytokines even less Treg developed. In neonates, when practically no recirculating Treg were found in the thymus, the absence of IL-2 led to substantially more reduced Treg-development than deficiency in IL-15. IL-2 and IL-15 differentially modulated the CD25, GITR, OX40, and CD73-phenotypes of thymus-egress-competent and periphery-seeding Treg. Interestingly, IL-2 and IL-15 also modulated the TCR-repertoire expressed by developing Treg. Upon transfer into Treg-less Foxp3sf mice, thymus-exit-competent Treg from IL-2- (and to a lesser extent IL-15-) deficient mice suppressed immunopathology less efficiently than wt Treg. Taken together, our results firmly establish important non-redundant quantitative and qualitative roles for IL-2 and, to a lesser extent, IL-15 in intrathymic Treg-development.
2022-08-29 | GSE153484 | GEO
Project description:IL-2 and IL-15 drive intrathymic development of distinct periphery-seeding CD4+Foxp3+ regulatory T lymphocytes
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Project description:Comparisons between untreated primary cells T-cell precursors from the thymus. CD69- thymocytes are from Zap70-deficent mice and are >95% CD4+CD8+. These cells fail to generate intrathymic TCR signals as a result of their lacking Zap70 molecules, and are thus representative of "preselection" CD4+CD8+ thymocytes. The CD69hi population comes from wildtype mice and is heterogeneous for CD4 and CD8 expression. These cells have been intrathymically TCR-signaled and are undergoing selection.
2010-06-10 | E-GEOD-2262 | biostudies-arrayexpress
Project description:Comparisons between untreated primary cells T-cell precursors from the thymus. CD69- thymocytes are from Zap70-deficent mice and are >95% CD4+CD8+. These cells fail to generate intrathymic TCR signals as a result of their lacking Zap70 molecules, and are thus representative of "preselection" CD4+CD8+ thymocytes. The CD69hi population comes from wildtype mice and is heterogeneous for CD4 and CD8 expression. These cells have been intrathymically TCR-signaled and are undergoing selection. Keywords: other
2005-03-07 | GSE2262 | GEO
Project description:Surveillance and defense of the enormous mucosal interface with the nonsterile world is critical to protecting the host from a wide range of pathogens. Chlamydia trachomatis (Ct) is an intracellular bacterial pathogen that replicates almost exclusively in the epithelium of the reproductive tract. The fallopian tubes and vagina seem poorly suited to surveillance and defense as they have limited immune infrastructure positioned near the epithelium. However, a dynamic process during clearing primary infections leaves behind new immune infrastructure positioned near epithelium. Memory lymphocyte clusters (MLC) harboring tissue resident memory T cells (TRM) are presumed to play an important role in protection from subsequent infections. Histologically Chlamydia MLC appear to be based on B cells. We therefore investigated B cell populations in the murine genital tract post-clearance of C. muridarum infections and the nature of T cells recovered from immune mice using immune B cells as antigen presenting cells (APC). These studies revealed a plasma B cell population in the genital tract consistent with histopathology seen in mouse and human Chlamydia infections, and discovery of a novel CD4 T cell subset based on production of IFN-ɣ and IL-13. We discuss these results in the context of Trm and previously published data showing that in humans a peripheral blood mononuclear IL-13 response to elementary bodies (EB) predicts resistance to future infection.
2017-12-01 | GSE104743 | GEO
Project description:Interferon dependent genes of intrathymic antigen presenting cells
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Project description:Circular RNAs (circRNAs) are stable single stranded RNA molecules which form a covalently closed continuous loop. They are involved in multiple biological processes, functioning mainly through interactions with microRNAs and proteins or by the expression of specific peptides. Preliminary data exist on circRNA expression in different peripheral blood cell populations. Deregulation of circRNAs has been shown to be key in the development of T-cell acute lymphoblastic leukemia (T-ALL). However, a detailed analysis on circRNAs expression in intrathymic thymocyte populations was still missing and might be key to understanding thymus development as well as tumours arising in the lymphoblastic line. The aim of this study was to investigate whether circRNAs are differentially expressed in thymocytes at different maturational stages during the intrathymic differentiation process.
2022-04-27 | GSE178889 | GEO
Project description:The cytokine IL-2 determines T cell fate by controlling T cell proliferation and differentiation, but the expression files of IL-2 regulated genes are not defined; Using Affymetrix mouse genome array and mouse T cell line CTLL-2, we analyzed the expression profiles of IL-2 regulated genes over 10 time points in 24 hours after IL-2 treatment. A total of 2,813 genes were differentially expressed (>=2-fold change) at least at one time point in response to IL-2 stimulation. Clustering analyses showed that these genes consist of 9 clusters, suggesting that the IL-2 regulated genes in mouse T cells have 9 expression patterns. These genes involve in many biological processes, including immune response, signal transduction, apoptosis, cell cycle, transcription, transport, biosynthesis and various metabolisms. Two supplementary tables are linked to this series:; Table 1: IL-2 responsive genes over the first 24 hours post-stimulation; Table 2: Newly identified IL-2 regulated genes function in a variety of biological processes Experiment Overall Design: Murine cytotoxic T lymphocyte cell line CTLL-2, derived from a C57BL/6 mouse, is an IL-2 dependent cell line. Cells were cultured in D10 medium in an incubator with 5% CO2 at 37oC to mid-log phase (~2 X 105 cells/mL), and collected by centrifugation, washed with phosphate buffered saline (PBS) (Invitrogen), resuspended at 1 X 106 cells/mL in the medium without IL-2 (IL-2 starvation) and cultured for 14 hours (No IL-2 stimulation, T0, 5 reps). After adding human rIL-2 (100 U/mL, Chiron, IL-2 stimulation), cells were collected at time point 0.5, 1, 2, 4, 6, 8, 10, 12, 16 and 24 hours, at least 3 biological replicates were carried out for each time point.Total RNA were extracted from the cells and was hybridized on Affymetrix GeneChip Mouse Genome 430 2.0 Array.
2008-11-22 | E-GEOD-6085 | biostudies-arrayexpress
Project description:Pleiotropic functions of miRNAs as transcriptional repressors have been reported for multiple biological processes. One prominent miRNA family is the miR-15 family, which is a well-established tumor-suppressor in B-cell chronic lymphocytic leukemia (CLL). The miR-15 family consists of three bicistronic clusters, miR-15a/16-1, miR-15b/16-2 and miR-497/195, all sharing the same seed sequence suggesting that loss one cluster can be functionally compensated by the remaining miR-15 family members. Thus, a combined deletion may be necessary to reveal its physiological function in vivo. A combined knockout of the most prominent miR-15 clusters, miR-15a/16-1 and miR-15b/16-2 in the hematopoietic system reveals a novel role of the miR-15 family in early B cell development highlighted by an increase of the pro-B cell compartment. Mechanistically, this effect is mediated by enhanced IL-7 receptor expression, which we identified as direct miR-15 target gene. Notably, elevated IL-7 receptor levels were sufficient to trigger increased activation of the STAT5 and PI3K/AKT pathways. Moreover, derepression of directly targeted cell cycle regulators such as Ccne1, Chek1 and Wee1 further facilitates G-to-S transition. Thus, by deregulating a target gene network of cell cycle and signaling mediators, loss of the miR-15 family establishes a pro-proliferative milieu manifesting in an enlarged pro-B cell pool.
2022-06-09 | GSE201238 | GEO