SciCombinator

Discover the most talked about and latest scientific content & concepts.

Concept: Naive T cell

36

Despite their importance, the molecular circuits that control the differentiation of naive T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based perturbation tools to systematically derive and experimentally validate a model of the dynamic regulatory network that controls the differentiation of mouse TH17 cells, a proinflammatory T-cell subset that has been implicated in the pathogenesis of multiple autoimmune diseases. The TH17 transcriptional network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, the coupled action of which may be essential for maintaining the balance between TH17 and other CD4+ T-cell subsets. Our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles; it also highlights novel drug targets for controlling TH17 cell differentiation.

Concepts: DNA, Gene, Gene expression, Algorithm, Cell type, T cell, T cells, Naive T cell

29

The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T-cell fate decisions. The activation of mTOR, which is the catalytic subunit of the mTORC1 and mTORC2 complexes, delivers an obligatory signal for the proper activation and differentiation of effector CD4(+) T cells, whereas in the regulatory T-cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg-cell de novo differentiation and population expansion. However, whether mTOR signalling affects the homeostasis and function of Treg cells remains largely unexplored. Here we show that mTORC1 signalling is a pivotal positive determinant of Treg-cell function in mice. Treg cells have elevated steady-state mTORC1 activity compared to naive T cells. Signals through the T-cell antigen receptor (TCR) and interleukin-2 (IL-2) provide major inputs for mTORC1 activation, which in turn programs the suppressive function of Treg cells. Disruption of mTORC1 through Treg-specific deletion of the essential component raptor leads to a profound loss of Treg-cell suppressive activity in vivo and the development of a fatal early onset inflammatory disorder. Mechanistically, raptor/mTORC1 signalling in Treg cells promotes cholesterol and lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg-cell proliferation and upregulation of the suppressive molecules CTLA4 and ICOS to establish Treg-cell functional competency. By contrast, mTORC1 does not directly affect the expression of Foxp3 or anti- and pro-inflammatory cytokines in Treg cells, suggesting a non-conventional mechanism for Treg-cell functional regulation. Finally, we provide evidence that mTORC1 maintains Treg-cell function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Treg cells to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg-cell suppressive activity in immune homeostasis and tolerance.

Concepts: Immune system, Protein, Metabolism, T cell, T cells, Major histocompatibility complex, T cell receptor, Naive T cell

5

Psoriasis is a complex disease of skin with a prevalence of about 2%. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for psoriasis to date, including data from eight different Caucasian cohorts, with a combined effective sample size >39,000 individuals. We identified 16 additional psoriasis susceptibility loci achieving genome-wide significance, increasing the number of identified loci to 63 for European-origin individuals. Functional analysis highlighted the roles of interferon signalling and the NFκB cascade, and we showed that the psoriasis signals are enriched in regulatory elements from different T cells (CD8(+) T-cells and CD4(+) T-cells including TH0, TH1 and TH17). The identified loci explain ∼28% of the genetic heritability and generate a discriminatory genetic risk score (AUC=0.76 in our sample) that is significantly correlated with age at onset (p=2 × 10(-89)). This study provides a comprehensive layout for the genetic architecture of common variants for psoriasis.

Concepts: DNA, Genetics, Mathematics, T helper cell, T cell, T cells, Genome-wide association study, Naive T cell

4

The processes regulating peripheral naive T-cell numbers and clonal diversity remain poorly understood. Conceptually, homeostatic mechanisms must fall into the broad categories of neutral (simple random birth-death models), competition (regulation of cell numbers through quorum-sensing, perhaps via limiting shared resources), adaptation (involving cell-intrinsic changes in homeostatic fitness, defined as net growth rate over time), or selection (involving the loss or outgrowth of cell populations deriving from intercellular variation in fitness). There may also be stably maintained heterogeneity within the naive T-cell pool. To distinguish between these mechanisms, we confront very general models of these processes with an array of experimental data, both new and published. While reduced competition for homeostatic stimuli may impact cell survival or proliferation in neonates or under moderate to severe lymphopenia, we show that the only mechanism capable of explaining multiple, independent experimental studies of naive CD4+ and CD8+ T-cell homeostasis in mice from young adulthood into old age is one of adaptation, in which cells act independently and accrue a survival or proliferative advantage continuously with their post-thymic age. However, aged naive T cells may also be functionally impaired, and so the accumulation of older cells via ‘conditioning through experience’ may contribute to reduced immune responsiveness in the elderly.

Concepts: Natural selection, Middle age, T cell, T cells, Gerontology, Old age, Ageing, Naive T cell

3

Naive T cells have long been regarded as a developmentally synchronized and fairly homogeneous and quiescent cell population, the size of which depends on age, thymic output and prior infections. However, there is increasing evidence that naive T cells are heterogeneous in phenotype, function, dynamics and differentiation status. Current strategies to identify naive T cells should be adjusted to take this heterogeneity into account. Here, we provide an integrated, revised view of the naive T cell compartment and discuss its implications for healthy ageing, neonatal immunity and T cell reconstitution following haematopoietic stem cell transplantation.

Concepts: Human, Stem cell, T cell, T cells, Heterogeneity, Homogeneity, Thymus, Naive T cell

1

Characterising the longevity of immunological memory requires establishing the rules underlying the renewal and death of peripheral T cells. However, we lack knowledge of the population structure and how self-renewal and de novo influx contribute to maintenance of memory compartments. Here, we characterise the kinetics and structure of murine CD4 T cell memory subsets by measuring the rates of influx of new cells and using detailed timecourses of DNA labelling that also distinguish the behaviour of recently divided and quiescent cells. We find that both effector and central memory CD4 T cells comprise subpopulations with highly divergent rates of turnover, and show that inflows of new cells sourced from the naive pool strongly impact estimates of memory cell lifetimes and division rates. We also demonstrate that the maintenance of CD4 T cell memory subsets in healthy mice is unexpectedly and strikingly reliant on this replenishment.

Concepts: Immune system, DNA, Gene, T helper cell, T cell, T cells, T cell receptor, Naive T cell

0

Retinoic acid-related orphan receptor γt (RORγt) is a key master regulator of the differentiation and activation of IL-17 producing CD4+ Th17, CD8+ Tc17 and IL-17/IFN-γ co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, RORγt is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective RORγt inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01-10 μM without affecting the production of IFN-γ. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells differentiation from naive T cells and memory CD4+ T cells at 100 nM without affecting Th1 cells differentiation. In addition, TAK-828F improved Th17/Treg cells population ratio by inhibiting Th17 cells differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-γ production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against RORγt both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells differentiation and improving imbalance between Th17 and Treg cells.

Concepts: Immune system, Pharmacology, T cell, T cells, Ulcerative colitis, Inflammatory bowel disease, Agonist, Naive T cell

0

A substantial proportion of patients with acute graft-versus-host disease (aGVHD) respond to cell therapy with culture-expanded human bone marrow mesenchymal stromal/stem cells (BM-MSCs). However, the mechanisms by which these cells can ameliorate aGVHD-associated complications remain to be clarified. We show here that BM-MSC-derived extracellular vesicles (EVs) recapitulated the therapeutic effects of BM-MSCs against aGVHD. Systemic infusion of human BM-MSC-derived EVs prolonged the survival of mice with aGVHD and reduced the pathologic damage in multiple GVHD-targeted organs. In EV-treated GVHD mice, CD4+ and CD8+ T cells were suppressed. Importantly, the ratio of CD62L-CD44+ to CD62L+CD44- T cells was decreased, suggesting that BM-MSC-derived EVs suppressed the functional differentiation of T cells from a naive to an effector phenotype. BM-MSC-derived EVs also preserved CD4+CD25+Foxp3+ regulatory T cell populations. In a culture of CD3/CD28-stimulated human peripheral blood mononuclear cells (PBMCs) with BM-MSC-derived EVs, CD3+ T cell activation was suppressed. However, these cells were not suppressed in cultures with EVs derived from normal human dermal fibroblasts (NHDFs). NHDF-derived EVs did not ameliorate the clinical or pathological characteristics of aGVHD in mice, suggesting an immunoregulatory function unique to BM-MSC-derived EVs. Microarray analysis of microRNAs in BM-MSC-derived EVs versus NHDF-derived EVs showed up-regulation of miR-125a-3p and down-regulation of cell proliferative processes, as identified by Gene Ontology enrichment analysis. Collectively, our findings provide the first evidence that amelioration of aGVHD by therapeutic infusion of BM-MSC-derived EVs is associated with the preservation of circulating naive T cells, possibly due to the unique microRNA profiles of BM-MSC-derived EVs. This article is protected by copyright. All rights reserved.

Concepts: Gene, Stem cell, Bone marrow, Graft-versus-host disease, T cell, T cells, PBMC, Naive T cell

0

Interleukin-22 (IL22) is one of the members of IL10 family. Elevated levels of this cytokine can be seen in diseases caused by T lymphocytes, such as Psoriasis, Rheumatoid arthritis, interstitial lung diseases. IL22 is produced by different cells in both innate and acquired immunities. Different types of T cells are able to produce IL22, but the major IL22-producing T-cell is the TCD4. TH22 cell is a new line of TCD4 cells, which differentiated from naive T cells in the presence of TNFα and IL6; 50% of peripheral blood IL22 is produced by these cells. IL22 has important functions in host defense at mucosal surfaces as well as in tissue repair. In this review, we assess the current understanding of this cytokine and focus on the possible roles of IL-22 in autoimmune diseases.

Concepts: Immune system, Inflammation, White blood cell, Infection, Rheumatoid arthritis, T cell, Naive T cell

0

The mechanisms leading to autoimmune and inflammatory diseases in the CNS have not been elucidated. The environmental triggers of the aberrant presence of CD4(+) T cells in the CNS are not known. In this article, we report that abnormal β-catenin expression in T cells drives a fatal neuroinflammatory disease in mice that is characterized by CNS infiltration of T cells, glial activation, and progressive loss of motor function. We show that enhanced β-catenin expression in T cells leads to aberrant and Th1-biased T cell activation, enhanced expression of integrin α4β1, and infiltration of activated T cells into the spinal cord, without affecting regulatory T cell function. Importantly, expression of β-catenin in mature naive T cells was sufficient to drive integrin α4β1 expression and CNS migration, whereas pharmacologic inhibition of integrin α4β1 reduced the abnormal T cell presence in the CNS of β-catenin-expressing mice. Together, these results implicate deregulation of the Wnt/β-catenin pathway in CNS inflammation and suggest novel therapeutic strategies for neuroinflammatory disorders.

Concepts: Inflammation, Medicine, Gene, Cell nucleus, Enzyme, T cell, T cells, Naive T cell