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8 recordsLinked to original sources
PubMed2025

Donor MHC-specific thymus vaccination allows for immunocompatible allotransplantation.

Organ transplantation is the last-resort option to treat organ failure. However, less than 10% of patients benefit from this only option due to lack of major histocompatibility complex (MHC)-matched donor organs and 25%-80% of donated organs could not find MHC-matched recipients. T cell allorecognition is the principal mechanism for allogeneic graft rejection. We herein present a "donor MHC-specific thymus vaccination" (DMTV) strategy to induce T cell tolerance to both autologous and allogeneic donor MHC. Allogeneic MHC molecules were expressed in the recipient thymus through adeno-associated virus-mediated delivery, which led to stable expression of allogeneic MHC together with the autologous MHC in the engineered thymus. During local T cell education, those T cells recognizing either autologous MHC or allogeneic MHC were equally depleted. We constructed C57BL/6-MHC and BALB/c-MHC dual immunocompatible mice via thymus vaccination of C57BL/6-MHC into the BALB/c thymus and observed long-term graft tolerance after transplantation of C57BL/6 skin and C57BL/6 mouse embryonic stem cells into the vaccinated BALB/c mice. We also validated our DMTV strategy in a bone marrow, liver, thymus (BLT)-humanized mouse model for immunocompatible allotransplantation of human embryonic stem cells. Our study suggests that the DMTV strategy is a potent avenue to introduce a donor compatible immune system in recipients, which overcomes the clinical dilemma of the extreme shortage of MHC-matched donor organs for treating patients with end-stage organ failure.

Animals↗
PubMed2026

Improved protocol for isolation and characterization of human thymic epithelial cells.

Thymic epithelial cells (TECs) play a vital role in the generation of immunocompetent and immunotolerant T cells. The understanding of TEC biology in model animals such as mice has advanced thanks to the cellular and molecular analyses of purified TEC populations, including cortical TECs (cTECs) and medullary TECs (mTECs). On the other hand, studies of human TECs have fallen behind because of the lack of a well-established method for purifying TEC populations. Here, we show that using 0.5 U/mL liberase to digest thymus tissue into single cells is quicker than using collagenase D or 0.1 U/mL liberase. Thymus digestion with 0.5 U/ml liberase preserves CD205 expressed by cTECs. RNA sequencing analysis of TEC populations isolated from 0.5 U/mL liberase-digested human thymic tissue revealed the expression of molecules known as cTEC- and mTEC-specific genes in mouse thymus in each human TEC population. Our study is expected to fuel further cellular and molecular studies of human TECs, including those related to the collapse of immune tolerance in humans.

Flow cytometry↗
PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗
PubMed2025

Elevated triglyceride-glucose index and risk of thymoma-associated myasthenia gravis: a prospective analysis from the UK Biobank.

BACKGROUND: Thymoma-associated myasthenia gravis (MG) is a clinically significant but uncommon condition, affecting up to half of thymoma patients and associated with worse outcomes than either disease alone. Reliable biomarkers for early risk stratification remain scarce. The triglyceride-glucose (TyG) index and triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio are established biomarkers reflecting insulin resistance and dyslipidemia. However, their clinical associations with thymoma-associated MG remain incompletely characterized. METHODS: A total of 501,954 UK Biobank participants were included. After exclusions, 422,397 (313 cases) were analyzed for TyG index and 422,691 (314 cases) for TG/HDL-C ratio. Exposures were stratified into quartiles, and assessed continuously per unit increase. Cox proportional hazards models estimated hazard ratios (HRs), restricted cubic splines (RCS) assessed non-linear associations, and subgroup analyses were stratified by body mass index (BMI). Sensitivity analyses examined TyG index and MG alone. RESULTS: An elevated TyG index was associated with increased risk of thymoma-associated MG. Compared to Q1, Q4 had higher risk (HR = 1.66, 95% CI: 1.20-2.31, P = 0.003); the overall HR per unit increase was 1.42 (95% CI: 1.17-1.73, P = 0.0005). TG/HDL-C ratio showed similar patterns: Q4 vs Q1 HR = 1.54 (95% CI: 1.11-2.15, P = 0.01); overall HR per unit increase was 1.06 (95% CI: 1.02-1.10, P = 0.002). Non-linear relationships were observed, with suggested inflection points at TyG index 8.7 and TG/HDL-C ratio 2.8, rather than strict thresholds. Subgroup analyses revealed stronger associations in normal-weight and obese participants, although tests for interaction were not statistically significant. Sensitivity analyses confirmed consistent associations between TyG index and MG risk, including for isolated MG. CONCLUSION: Elevated TyG index and TG/HDL-C ratio were independently associated with higher thymoma-associated MG risk in this large prospective cohort, with evidence of non-linear relationships and BMI-related heterogeneity. These findings provide novel epidemiologic evidence linking metabolic markers of insulin resistance with thymoma-associated MG, but clinical translation requires further validation.

Humans↗
PubMed2025

Perinatal dysfunction of innate immunity in cystic fibrosis.

In patients with cystic fibrosis (CF), repeated cycles of infection and inflammation eventually lead to fatal lung damage. Although diminished mucus clearance can be restored by highly effective CFTR modulator therapy, inflammation and infection often persist. To elucidate the role of the innate immune system in CF etiology, we investigated a CF pig model and compared these results with those for preschool children with CF. In newborn CF pigs, we observed changes in lung immune cell composition before the onset of infection that were dominated by increased monocyte infiltration, whereas neutrophil numbers remained constant. Flow cytometric and transcriptomic profiling revealed that the infiltrating myeloid cells displayed a more immature status. Cells with comparably immature transcriptomic profiles were enriched in the blood of CF pigs at birth as well as in preschool children with CF. This pattern coincided with decreased CD16 expression in the myeloid cells of both pigs and humans, which translated into lower phagocytic activity and reduced production of reactive oxygen species in both species. These results were indicative of a congenital, translationally conserved, and functionally relevant aberration of the immune system in CF. In newborn wild-type pigs, CFTR transcription in immune cells, including lung-derived and circulating monocytes, isolated from the bone marrow, thymus, spleen, and blood was below the detection limits of highly sensitive assays, suggesting an indirect etiology of the observed effects. Our findings highlight the need for additional immunological treatments to target innate immune deficits in patients with CF.

Cystic Fibrosis↗
PubMed2026

A tumor suppressor role of the miR-15b/16-2 cluster in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy arising from the neoplastic transformation of immature T cells during their development in the thymus. Deciphering the developmental programs whose dysregulation drives T-ALL pathogenesis is critical for the development of novel targeted therapies, which remain an urgent unmet need for the treatment of this disease. MicroRNAs (miRNAs) have emerged as key posttranscriptional regulators of numerous physiological processes, including cancer. However, the specific role of miRNAs in human T-cell development and T-ALL pathogenesis remains largely unexplored. In this study, we comprehensively evaluated miRNA expression profiles across human T-cell development using microarray analysis and identified a dynamic expression pattern of miR-16-2, which is upregulated during early pre-T-cell proliferative stages up to the resting stage of immature thymocytes immediately preceding T-cell receptor αβ expression and is subsequently downregulated. We also confirmed the coordinated regulation of miR-15b expression, consistent with the reported clustered genomic location of both miRNAs. Notably, functional studies identified the miR-15b/16-2 cluster as a negative regulator of early thymocyte proliferation and demonstrated that overexpression of miR-15b/16-2 in T-ALL cells impaired leukemic growth in vitro and tumor progression in patient-derived xenotransplantation assays. Mechanistically, miR-15b/16-2 represses the expression of the genes encoding BCL-2 and cyclin D3, thereby promoting apoptosis and cell cycle dysregulation in T-ALL cells, characterized by an accumulation of G0-phase cells and a defective transition to the G2/M phase. Overall, these findings support a novel tumor-suppressive function for miR-15b/16-2 in T-ALL and highlight its potential as a promising therapeutic target.

MicroRNAs↗
PubMed2020

Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice.

Senescent cells accumulate with age in vertebrates and promote aging largely through their senescence-associated secretory phenotype (SASP). Many types of stress induce senescence, including genotoxic stress. ERCC1-XPF is a DNA repair endonuclease required for multiple DNA repair mechanisms that protect the nuclear genome. Humans or mice with reduced expression of this enzyme age rapidly due to increased levels of spontaneous, genotoxic stress. Here, we asked whether this corresponds to an increased level of senescent cells. p16Ink4a and p21Cip1 mRNA were increased ~15-fold in peripheral lymphocytes from 4- to 5-month-old Ercc1-/∆ and 2.5-year-old wild-type (WT) mice, suggesting that these animals exhibit a similar biological age. p16Ink4a and p21Cip1 mRNA were elevated in 10 of 13 tissues analyzed from 4- to 5-month-old Ercc1-/∆ mice, indicating where endogenous DNA damage drives senescence in vivo. Aged WT mice had similar increases of p16Ink4a and p21Cip1 mRNA in the same 10 tissues as the mutant mice. Senescence-associated β-galactosidase activity and p21Cip1 protein also were increased in tissues of the progeroid and aged mice, while Lamin B1 mRNA and protein levels were diminished. In Ercc1-/Δ mice with a p16Ink4a luciferase reporter, bioluminescence rose steadily with age, particularly in lung, thymus, and pancreas. These data illustrate where senescence occurs with natural and accelerated aging in mice and the relative extent of senescence among tissues. Interestingly, senescence was greater in male mice until the end of life. The similarities between Ercc1-/∆ and aged WT mice support the conclusion that the DNA repair-deficient mice accurately model the age-related accumulation of senescent cells, albeit six-times faster.

Aging↗
PubMed2026

Inhibition of the atypical kinase WNK1 as a therapeutic strategy in TAL-related T-cell acute lymphoblastic leukemia.

Driver mutations in T-cell acute lymphoblastic leukemia (T-ALL) rarely affect druggable kinases. However, these kinases can be aberrantly activated or repressed as secondary oncogenic events. Thus, integrating unbiased phosphoproteomics with genomic approaches may offer novel opportunities for target discovery and therapeutic interventions. In our study, we identified WNK1 (with no lysine [K]) as a potential target in T-ALL by pairing a list of vulnerable kinases with data from a phosphoproteomic screen of T-ALL cell lines. We subsequently validated WNK1 by loss-of-function-based studies and tested WNK inhibitors in several in vitro and in vivo T-ALL models and clinical T-ALL samples. We showed that therapeutic WNK1 repression promotes polyploidy, resulting in cell proliferation arrest, and morphometric changes, such as incomplete cell division or chromosome segregation through altered mitotic spindle assembly and abscission defects. Furthermore, we found that WNK1 is overexpressed in the TAL1/2-related subgroup, but not in normal thymus or lymph nodes, suggesting a potential translational area for clinical exploitation in poor-prognosis T-ALL carrying PTEN mutations and del(6q). Our work also reports a functional contribution of WNK1 in the leukemia establishment and progression. Structurally WNK1 is an atypical serine/threonine kinase that diverges from canonical kinases by lacking the conserved lysine in subdomain II, instead featuring a cysteine in subdomain I, which is critical for adenosine triphosphate (ATP) binding. This unusual structural configuration creates a distinct ATP-binding pocket with limited sequence similarity to conventional kinases, offering a unique opportunity to develop highly selective small molecules. Targeting this atypical ATP domain could thus provide a therapeutic advantage and broaden the treatment landscape for T-ALL.

WNK Lysine-Deficient Protein Kinase 1↗