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摘要： Regulatory T cells (T-reg) are critical players of immune tolerance that develop in the thymus via two distinct developmental pathways involving CD25(+)Foxp3(-) and CD25(-)Foxp3(lo) precursors. However, the mechanisms regulating the recently identified Foxp3(lo) precursor pathway remain unclear. Here, we find that the membrane-bound lymphotoxin alpha(1)beta(2) (LT alpha(1)beta(2)) heterocomplex is upregulated during T-reg development upon TCR/CD28 and IL-2 stimulation. We show that Lta expression limits the maturational development of T-reg from Foxp3(lo) precursors by regulating their proliferation, survival, and metabolic profile. Transgenic reporter mice and transcriptomic analyses further reveal that medullary thymic epithelial cells (mTEC) constitute an unexpected source of IL-4. We demonstrate that LT alpha(1)beta(2)-lymphotoxin beta receptor-mediated interactions with mTEC limit T-reg development by down-regulating IL-4 expression in mTEC. Collectively, our findings identify the lymphotoxin axis as the first inhibitory checkpoint of thymic T-reg development that fine-tunes the Foxp3(lo) T-reg precursor pathway by limiting IL-4 availability.

关键词： Pathology  

摘要： IL-6 (interleukin-6) is an essential cytokine that participates in many inflammatory and immune responses, and disrupting the interaction between IL-6 and its receptor sIL-6R (soluble form of IL-6 receptor) represents a promising treatment strategy for inflammation and related diseases. Herein we report the first-ever effort of evolving a bispecific circular aptamer, named CIL-6A6-1, that is capable of binding both IL-6 and sIL-6R with nanomolar affinities and is stable in serum for more than 48 hours. CIL-6A6-1 can effectively block the IL-6/sIL-6R interaction and significantly inhibit cell inflammation. Most importantly, this bispecific aptamer is much more effective than aptamers that bind IL-6 and sIL-6R alone as well as tocilizumab, a commercially available humanized monoclonal antibody against sIL-6R, highlighting the advantage of selecting bispecific circular aptamers as molecular tools for anti-inflammation therapy. Interestingly, CIL-6A6-1 is predicted to adopt a unique structural fold with two G-quadruplex motifs capped by a long single-stranded region, which differs from all known DNA aptamers. This unique structural fold may also contribute to its excellent functionality and high stability in biological complex media. We anticipate that our study will represent a significant step forward towards demonstrating the practical utility of bispecific DNA aptamers for therapeutic applications. We report a circular DNA aptamer isolated from a synthetic DNA library to bind both IL-6 and sIL-6R with nanomolar affinities. This aptamer can effectively block the IL-6/sIL-6R interaction and significantly inhibit cell inflammation.

关键词： chronic lymphocytic leukemia   IL1 receptor antagonist   interferon   signal transduction  

摘要： Nuclear factor kappa B (NFκB) is a pathogenic factor in chronic lymphocytic leukemia (CLL) that is not addressed specifically by current therapies. NFκB is activated by inflammatory factors that stimulate toll-like receptors (TLRs) and receptors for interleukin-1 (IL-1) family members. IL-1 is considered a master regulator of inflammation, and IL-1 receptor signaling is inhibited by the IL-1 receptor antagonist anakinra. These considerations suggested that anakinra might have a role in the treatment of CLL. Consistent with this idea, anakinra inhibited spontaneous and TLR7-mediated activation of the canonical NFκB pathway in CLL cells in vitro. However, CLL cells exhibited only weak signaling responses to IL-1 itself, and anakinra was found to inhibit NFκB along with oxidative stress in an IL-1 receptor-independent manner. Anakinra was then administered with minimal toxicity to 11 previously untreated CLL patients in a phase I dose-escalation trial (NCT04691765). A stereotyped clinical response was observed in all patients. Anakinra lowered blood lymphocytes and lymph node sizes within the first month that were associated with downregulation of NFκB and oxidative stress in the leukemia cells. However, inhibition of NFκB was accompanied by upregulation of type 1 interferon (IFN) signaling, c-MYC-regulated genes and proteins, and loss of the initial clinical response. Anakinra increased IFN signaling and survival of CLL cells in vitro that were, respectively, phenocopied by mitochondrial antioxidants and reversed by IFN receptor blocking antibodies. These observations suggest that anakinra has activity in CLL and may be a useful adjunct for conventional therapies as long as compensatory IFN signaling is blocked at the same time. Copyright © 2024 the Author(s).

关键词： 胰高血糖素样肽-1   T淋巴细胞功能障碍   脓毒症   免疫代谢  

摘要： 脓毒症晚期发生持续性炎症反应、免疫抑制和分解代谢综合征(PICS)，而T淋巴细胞功能障碍是PICS的重要特征。T淋巴细胞的营养代谢状态严重影响其免疫功能。脓毒症时各种信号分子包括营养素，通过磷脂酰肌醇-3激酶(PI3K)-丝氨酸/苏氨酸激酶(Akt)-哺乳动物雷帕霉素靶蛋白(mTOR)信号通路促进T淋巴细胞发生代谢重编程，从而改变其免疫表型。胰高血糖素样肽-1(GLP-1)是一种调节物质和能量代谢的胰泌素，具有降糖、免疫抑制和抗炎的作用，脓毒症时其水平急剧升高，并与危重患者的病情和预后密切相关。GLP-1受体(GLP-1R)激动剂可阻断T淋巴细胞的糖酵解，抑制葡萄糖转运蛋白mRNA的表达，从而抑制T淋巴细胞增殖。因此，脓毒症时内源性GLP-1水平升高可能代表机体能量代谢向有氧糖酵解转换，反映的是PICS的一种病理状态。本文阐述GLP-1对脓毒症T淋巴细胞免疫功能和代谢重编程的调控作用，以为通过GLP-1R防治脓毒症T淋巴细胞功能障碍提供策略参考。

摘要： Studies comparing the efficacy of posttransplant cyclophosphamide (PTCy) to conventional calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis regimens in patients with Hodgkin lymphoma (HL) are scarce. This study aimed to compare the outcomes of patients with HL undergoing hematopoietic stem cell transplantation (HSCT) from HLA-matched donors who received GVHD prophylaxis with either PTCy- or conventional CNI-based regimens, using data reported in the European Society for Blood and Marrow Transplantation database between January 2015 and December 2022. Among the cohort, 270 recipients received conventional CNI-based prophylaxis and 176 received PTCy prophylaxis. Notably, PTCy prophylaxis was associated with delayed hematopoietic recovery but also with a lower risk of chronic (25% vs 43%;P < .001) and extensive chronic GVHD (13% vs 28%;P = .003) compared with the CNI-based cohort. The 2-year cumulative incidence of nonrelapse mortality and relapse was 11% vs 17% (P = .12) and 17% vs 30% (P = .007) for PTCy- and CNI-based, respectively. Moreover, the 2-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) were all significantly better in the PTCy group compared with the CNI-based group: 85% vs 72% (P = .005), 72% vs 53% (P < .001), and 59% vs 31% (P < .001), respectively. In multivariable analysis, PTCy was associated with a lower risk of chronic and extensive chronic GVHD, reduced relapse, and better OS, PFS, and GRFS than the CNI-based platform. Our findings suggest that PTCy as GVHD prophylaxis offers more favorable outcomes than conventional CNIbased prophylaxis in adult patients with HL undergoing HSCT from HLA-matched donors.

关键词： 老年   髋部骨折   术后低蛋白血症   中药单体   细胞因子   NF-κB信号通路  

摘要： 应激环境下机体的高分解代谢和炎性反应引起的微循环功能障碍，进而导致白蛋白渗漏，是造成老年髋部骨折术后低蛋白血症的重要原因。中药治疗低蛋白血症具有价格低廉，不良反应较少，安全性更高的优势。甘草、党参、黄芪、麦冬、川芎及茯苓等10余种中药单体能够通过干预NF-κB等信号通路，降低炎症细胞因子的产生，从而发挥抑制应激条件下机体炎症反应的作用。但目前对于中药单体干预的研究较为局限，如相关研究阶段仍停留在动物和细胞实验，缺乏系统的中医辨证施治研究，对于部分中药的药理学研究尚不完善，缺乏对中药单体干预低蛋白血症的其他信号通路或途径的可能作用。以中药有效活性成分靶向对抗炎症反应，治疗骨折术后低蛋白血症，具有巨大的发展潜力，通过深入探索这些活性成分的作用机制，为中医药在临床上的运用以及新药的研发提供有力的参考依据和创新思路。

关键词： Cereibacter   Rhodobacter   denitrificans   complete genome   IL106  

摘要： Cereibacter sphaeroides is a non-sulfur purple bacterium, one of the most versatile and thoroughly studied species of its kind, can grow on a variety of compounds photoheterotrophically, and is often used in bioremediation. We present the complete genome of Cereibacter sphaeroides f. sp. denitrificans underscoring its unique features.

关键词： antibody-mediated rejection   chimeric antigen receptor (CAR) therapy   donor-specific antibodies   HLA-specific B cells   long-lived plasma cells  

摘要： Antibody-mediated rejection (ABMR) is a significant obstacle to achieving optimal long-term outcomes after solid organ transplantation. The presence of donor-specific antibodies (DSAs), particularly against human leucocyte antigen (HLA), increases the risk of allograft rejection and subsequent graft loss. No effective treatment for ABMR currently exists, warranting novel approaches to target the HLA-specific humoral alloimmune response. Cellular therapies may hold promise to this end. According to publicly available sources as of now, three independent laboratories have genetically engineered a chimeric HLA antibody receptor (CHAR) and transduced it into human T cells, based on the demonstrated efficacy of chimeric antigen receptor T cell therapies in malignancies. These CHAR-T cells are designed to exclusively eliminate B cells that produce donor-specific HLA antibodies, which form the cornerstone of ABMR. CHAR technology generates potent and functional human cytotoxic T cells to target alloreactive HLA-specific B cells, sparing B cells with other specificities. Thus CHAR technology may be used as a selective desensitization protocol and to treat ABMR after solid organ transplantation.

关键词： Aryl Hydrocarbon Receptor   Cancer   Interferon Gamma   Tumor Immunity  

摘要： While immunotherapy has shown efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, (the aryl hydrocarbon receptor/AhR), a known but counterintuitive mediator of immunosuppression (IFNγ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk- and scRNA sequencing of LUADs and tumor-infiltrating leukocytes were used to map out a signaling pathway leading from IFNγ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that: IFNγ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 upregulation is mediated by the AhR in murine and human LUAD cells, AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR→IDO1→Kyn→AhR amplification loop, transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients. The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8 T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFNγ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.

关键词： Clonal hematopoiesis of indeterminate potential (CHIP)   aging   inflamm-aging   immunosenescence  

摘要： Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- -/- genotypes reconstituted with WT CD45.1* * and Tet2 - / - CD45.2 * HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2 - / - cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- -/- recipient mice, suggesting that TNF signaling is essential for the expansion Tet2- mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, , may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-- mutant CHIP.