The development of thymic regulatory T cells (Treg) is mediated by Aire-regulated self-antigen presentation on medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), but the cooperation between these cells is still poorly understood. Here we show that signaling through Toll-like receptors (TLR) expressed on mTECs regulates the production of specific chemokines and other genes associated with post-Aire mTEC development. Using single-cell RNA-sequencing, we identify a new thymic CD14+Sirpα+ population of monocyte-derived dendritic cells (CD14+moDC) that are enriched in the thymic medulla and effectively acquire mTEC-derived antigens in response to the above chemokines. Consistently, the cellularity of CD14+moDC is diminished in mice with MyD88-deficient TECs, in which the frequency and functionality of thymic CD25+Foxp3+ Tregs are decreased, leading to aggravated mouse experimental colitis. Thus, our findings describe a TLR-dependent function of mTECs for the recruitment of CD14+moDC, the generation of Tregs, and thereby the establishment of central tolerance.

/pdf/toll-like-receptor-signaling-in-thymic-epithelium-controls-29l6o7lale.pdf

Toll-like receptor signaling in thymic epithelium controls monocyte-derived dendritic cell recruitment and Treg generation.

Allogeneic hematopoietic stem cell (HSC) transplantation can cure patients suffering from diverse genetic and acquired diseases as well as cancers. Nevertheless, under conditions where T-cell reconstitution is critical, the entry of donor progenitors into the thymus remains a major bottleneck. It is assumed that following the intravenous injection of HSC, they first home to the BM. More committed progenitors can then be exported to the thymus in response to a myriad of signals regulating thymus seeding. Notably although, the thymus is not continually receptive to the import of hematopoietic progenitors. Furthermore, as stem cells with self-renewing capacity do not take up residence in the thymus under physiological conditions, the periodic colonization of the thymus is essential for the sustained differentiation of T lymphocytes. As such, we and others have invested significant efforts into exploring avenues that might foster a long-term thymus-autonomous differentiation. Here, we review strategic approaches that have resulted in long-term T-cell differentiation in immunodeficient (SCID) mice, even across histocompatibility barriers. These include the forced thymic entry of BM precursors by their direct intrathymic injection as well as the transplantation of neonatal thymi. The capacity of the thymus to support hematopoietic progenitors with renewal potential will hopefully promote the development of new therapeutic strategies aimed at enhancing T-cell differentiation in patients undergoing HSC transplantation.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.1378

Concise review: hematopoietic stem cell transplantation: targeting the thymus.

Background: Gene transfer in the thymus, based on HIV-derived lentiviral vectors, is a promising avenue for modulation of T cell selection and autoimmunity. However, the impact of intrathymic (IT) injections on an antigen-specific immune response elicited in the periphery of normal mice has not been investigated yet. Methods: Highly concentrated stocks of lentiviral vectors expressing the soluble form of hemaglutinin of the influenza virus (LvHA) were injected in the thymus of normal BALB/c mice. The CD4 and CD8-mediated immune responses to HA after peripheral immunization were measured by various parameters. Results: We first show that a lentiviral vector expressing the luciferase was detected for at least 2months after IT-injections. We then show that the LvHA vector could elicit a functional CD4- and CD8-T cell-mediated immune responses in the peripheral lymphoid organs of BALB/c mice. IT-injection of the LvHA vector significantly curbed this response: lower numbers of transferred HA-specific CD4 + T cells were found in LvHA-injected compared to control animals. Furthermore, lower frequencies of HA-specific CD8 + T cells, interferon γ-producing cells and cytotoxic cells were detected from 3weeks to 3months in LvHA-injected mice compared to controls. However, these reduced CD8-mediated responses were not increased after depletion of CD25 + cells in vitro or in vivo. Conclusions: The results obtained in the present study show that injection of the LvHA lentiviral vector significantly curtailed the immune response to the same antigen in the periphery. Increased selection of HA-specific regulatory T cells and negative selection of HA-specific CD8 + T cell precursors may explain the results. Our work establish the feasibility of IT-injections of lentiviral vectors to manipulate T cell tolerance in the thymus of normal mice, for basic and pre-clinical research.

Intrathymic injection of lentiviral vector curtails the immune response in the periphery of normal mice.

Small-scale but highly destructive harmful algal blooms (HABs) are increasingly observed in coastal aquaculture areas. However, the impact of elevated organic nutrients generated during mariculture production and their bioavailability for HABs are not yet fully understood. This study investigated the population dynamics of HAB-causing species and the hydrolytic dynamics of different extracellular enzyme activities (EEAs) along with variations in environmental inorganic and organic nutrients during a dinoflagellate bloom of Prorocentrum shikokuense adjacent to the coastal aquaculture area in Sansha Town, located in the East China Sea. The results indicated that both inorganic and organic nutrients were enriched in the study area, with organic nutrients comprising more than half of the total nutrient content. The presence of enriched organic nutrients and a high N:P ratio significantly contributed to bloom occurrence. Organic nutrient concentrations played a predominant role in controlling both the density and duration of the P. shikokuense bloom. The significant increase in EEAs during the bloom stages, primarily contributed by P. shikokuense, emphasized the crucial hydrolytic role of extracellular enzymes in nutrient recycling and supply for the bloom. The enzymatic kinetic parameters indicated enhanced efficiency in the recycling of organic nutrients as the bloom progressed. This study highlights the significant role of organic nutrients facilitated by EEAs in determining the occurrence, duration, and magnitude of HABs in coastal aquaculture areas. 

Organic nutrient availability and extracellular enzyme activity influence harmful algal bloom proliferation in a coastal aquaculture area

Abstract Naked mole-rats (NMRs) are best known for their extreme longevity and cancer resistance, suggesting that their immune system might have evolved to facilitate these phenotypes. Natural killer (NK) and T cells have evolved to detect and destroy cells infected with pathogens and to provide an early response to malignancies. While it is known that NMRs lack NK cells, likely lost during evolution, little is known about their T-cell subsets in terms of the evolution of the genes that regulate their function, their clonotypic diversity, and the thymus where they mature. Here we find, using single-cell transcriptomics, that NMRs have a large circulating population of γδT cells, which in mice and humans mostly reside in peripheral tissues and induce anti-cancer cytotoxicity. Using single-cell-T-cell-receptor sequencing, we find that a cytotoxic γδT-cell subset of NMRs harbors a dominant clonotype, and that their conventional CD8 αβT cells exhibit modest clonotypic diversity. Consistently, perinatal NMR thymuses are considerably smaller than those of mice yet follow similar involution progression. Our findings suggest that NMRs have evolved under a relaxed intracellular pathogenic selective pressure that may have allowed cancer resistance and longevity to become stronger targets of selection to which the immune system has responded by utilizing γδT cells. 

Evolution of T cells in the cancer-resistant naked mole-rat.

Intrathymic injection is a common technique used for research concerning immunotolerance induction, gene therapy and T cell development in mice. Traditionally used protocols involve major surgery that exposes the thoracic cavity, which results in injury to the mice and increased risk of poor recovery and postsurgical complications such as infection. We introduce a simplified intrathymic injection technique that does not expose the thoracic cavity and virtually eliminates pain, distress and postoperative complications while maintaining high injection efficiency. The technique is suitable for both adult and neonatal mice.

A simplified intrathymic injection technique for mice.

Phosphatases play a crucial role in recycling organic phosphorus and determining primary production and phytoplankton communities in seawater, especially in phosphate-depleted coastal waters. The present study analyzed spatiotemporal variation in phosphomonoesterase (PMEase) activity (PMEA) and phosphodiesterase (PDEase) activity (PDEA) during 2 dinoflagellate blooms occurring in 2 coastal areas of Fujian Province, East China Sea, which differed in external phosphate conditions. Together with environmental variables and with a specific focus on the availability of different phosphorus forms in the seawater, the regulation of both phosphatases was studied. The results showed that dissolved organic phosphorus (DOP) was the major phosphorus source during blooms, especially in phosphate-depleted environments. Labile DOP accounted for more than 50% of DOP, of which phosphomonoester (PME) and phosphodiester (PDE) accounted for 75-94% and 6-25%, respectively. PMEA and PDEA were highly correlated, both increasing during blooms with a fixed PMEA:PDEA ratio of 2.5 under external phosphate conditions at both sites. Both PMEA and PDEA were negatively correlated with dissolved inorganic phosphorus (DIP) when phosphate was depleted, but positively correlated with DOP regardless of external phosphate conditions. During dinoflagellate blooms, temperature and phytoplankton biomass were the dominant variables determining both phosphatase activities under phosphate-depleted conditions, whereas the availability of DOP was the dominant variable determining both phosphatase activities under phosphate-replete conditions. This study suggests the importance of phosphatases in recycling DOP, and indicates similar regulation of PMEA and PDEA during dinoflagellate blooms. 

Phosphomonoesterase and phosphodiesterase activities and their regulation during dinoflagellate blooms under different external phosphate conditions

The high proportion of renewable distributed power in the distribution network has a series of impacts on the safety and economy of the power grid. Based on the output characteristics and cost characteristics of distributed energy, this paper proposes the evaluation model of the aggregated output range of VPP and the quotation model of VPP. An optimization method is proposed to encourage distributed energy to participate in voltage regulation auxiliary services. In this paper, a multi-objective optimization method is presented, which takes minimizing system voltage deviation, network loss and auxiliary service cost as objectives. The Pareto solution set is solved by the improved particle swarm optimization algorithm. Taking an area with a high proportion of distributed energy as an example, the effectiveness of the model and algorithm is verified, the relationship between optimization objectives is discussed, and flexible optimization options are provided. 

Source-grid collaborated multi-objective optimization based on virtual power plant

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A simplified intrathymic injection technique for mice.

Phosphomonoesterase and phosphodiesterase activities and their regulation during dinoflagellate blooms under different external phosphate conditions

Source-grid collaborated multi-objective optimization based on virtual power plant