Mature T-cell Research Articles

Comprehensive genomic analysis reveals molecular heterogeneity in pediatric ALK-positive anaplastic large cell lymphoma.

Anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for 10-15% of childhood lymphomas. Despite the observation that more than 90% of pediatric cases harbor the anaplastic lymphoma kinase (ALK) rearrangement resulting in aberrant ALK kinase expression, there is significant clinical, morphologic, and biological heterogeneity. To gain insights into the genomic aberrations and molecular heterogeneity within ALK-positive ALCL (ALK+ ALCL), we analyzed 46 pediatric ALK+ ALCLs by whole-exome sequencing, RNA sequencing, and DNA methylation profiling. Whole-exome sequencing found on average 25 SNV/Indel events per sample with recurring genetic events in regulators of DNA damage (TP53, MDM4), transcription (JUNB), and epigenetic regulators (TET1, KMT2B, KMT2A, KMT2C, KMT2E). Gene expression and methylation profiling consistently subclassified ALK+ ALCLs into two groups characterized by differential ALK expression levels. The ALK-low group showed enrichment of pathways associated with immune response, cytokine signaling, and a hypermethylated predominant pattern compared to the ALK-high group, which had more frequent copy number changes and was enriched with pathways associated with cell growth, proliferation, and metabolism. Altogether, these findings suggest that there is molecular heterogeneity within pediatric ALK+ ALCL, predicting distinct biological mechanisms that may provide novel insights into disease pathogenesis and represent prognostic markers.

Haematogenous seeding in mycosis fungoides and Sézary syndrome: Current evidence and clinical implications.

Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of diseases characterised by abnormal neoplastic T-cell growth in the skin. Mycosis fungoides (MF), the most common CTCL, manifests as erythematous skin patches and/or plaques, tumours or erythroderma. The disease may involve blood, lymph nodes and rarely viscera. Sézary syndrome (SS) is a unique leukaemia/lymphoma syndrome related to MF, which presents with blood and skin involvement at diagnosis. The pathogenesis of MF/SS is not fully elucidated. The presence of skin lesions at distant sites underpins a hypothesis that MF/SS lesions may develop through haematogenous seeding. Phenotypic similarities between malignant and normal T-cells led to the notion that disease-initiating mutations occur in specific subtypes of mature T-cells, which are responsible for most CTCLs. However, this mature T-cell precursor model is not always consistent with clinical observations and research on MF/SS pathogenesis. Here, we review evidence supporting an alternative model of pathogenesis for MF/SS involving haematogenous seeding as a key process responsible for the initiation and progression of the disease. According to this hypothesis, malignant transformation occurs at an early stage of T-cell development (probably in bone marrow or thymus), yielding circulating neoplastic T-cells which colonise the skin where the microenvironment is most permissive for proliferation and evolution. These mutated precursor cells seed the skin where they find a suitable niche to develop into clinically perceptible disease. Subsequently, malignant T-cells can re-enter the bloodstream, re-seed pre-existing lesions and seed new areas of the skin, causing synchronous and convergent changes in the transcriptomic profile of lesions and tumours, and clinical disease progression - 'consecutive haematogenous seeding' captures this temporal phenomenon. This model radically changes the current understanding of CTCL pathogenesis, transforming it from a primarily cutaneous disease with secondary involvement of blood, to a systemic disease, where the spread of malignant cells through the blood to the skin is not a phenomenon of advanced disease but is an essential component of pathogenesis. This understanding of MF/SS could have several clinical implications, including standardising our approach to assessing blood tumour burden, potential advances in prognosis and monitoring, and investigating combination treatments to improve patient outcomes.

Global outcomes and prognosis for relapsed/refractory mature T-cell and NK-cell lymphomas: results from the PETAL consortium

AbstractVariances in global access to drugs and treatment practices make it challenging to understand the benefit of contemporary therapies in patients with relapsed and refractory (R/R) mature T-cell and natural killer–cell lymphomas (MTCL and MNKCL). We conducted an international retrospective cohort study of 925 patients with R/R MTCL and MNKCL. In peripheral T-cell lymphoma–not otherwise specified and anaplastic lymphoma kinase–negative anaplastic large cell lymphoma (ALK– ALCL), patients with relapsed lymphoma demonstrated a superior median overall survival (OS) relative to refractory from the time of second-line treatment. We identified several independent predictors of OS for R/R lymphoma including age >60 years, primary refractory disease, histological subtype other than angioimmunoblastic T-cell lymphoma (AITL), extranodal sites >1, Ki67 ≥40%, and absolute lymphocyte count less than the lower limit of normal. A multivariable model incorporating these formed the basis for a prognostic index for R/R TCL, in which patients are stratified into low-risk (0-1 risk factor), intermediate-risk (2-3 risk factors), or high-risk (≥4 risk factors) groups, which were associated with 3-year OS of 57.14%, 23.3%, and 7%, respectively. Patients received either a "novel" single agent (SA; 35%) or cytotoxic chemotherapy (CC; 60%) for their second-line treatment. Higher progression-free survival was observed with SA over CC for the entire cohort with a higher 3-year OS in AITL and ALK– ALCL. Among the SA, small-molecule inhibitors demonstrated OS advantage relative to CC in AITL. Our results highlight continued efficacy of novel drugs globally and the potential of a new prediction model in informing heterogeneous prognosis within the R/R population of MTCL and MNKCL.

T-Cell Phenotypes and Systemic Cytokine Profiles of People Living with HIV Admitted to Hospital with COVID-19.

Whether SARS-CoV-2 infection leads to a higher mortality and morbidity in people living with HIV (PLWH) in Africa remains inconclusive. In this study, we explored the differences in the T-cell phenotypes between people with and without HIV on the day of admission (V1) and ±7 days later (V2), as well as their cytokine/chemokine profiles on V1. Patients admitted with COVID-19 were recruited between May 2020 and December 2021 from the Steve Biko Academic and Tshwane District Hospitals in Pretoria, South Africa. Of 174 patients, 37 (21%) were PLWH. T-cell profiles were determined by flow cytometry, and cytokine levels were determined using a multiplex suspension bead array. PLWH were significantly younger than those without HIV, and were more likely to be female. In an adjusted analysis, PLWH had higher percentages of CD4+ central memory (CM) programmed cell death protein 1 (PD-1)+, CD8+ effector memory (EM)2, and CD8+ EM4 CD57+ cells, as well as higher concentrations of interleukin (IL)-35 at admission. PLWH with CD4+ T-cell counts of >200 cells/mm3 had altered CD4+ and CD8+ T-cell profiles, lower levels of systemic inflammation measured by plasma ferritin and PCT levels, and less severe disease. PLWH with CD4+ T-cell counts of <200 cells/mm3 on admission had higher concentrations of IL-6 and lower levels of IL-29. At V2, the percentages of CD4+ CM PD-1+ T-cells and CD8+ EM4 T-cells co-expressing CD57 and PD-1 remained higher in PLWH, while all other CD8+ EM populations were lower. Fewer CD8+ EM T-cells after ±7 days of admission may be indicative of mechanisms inhibiting EM T-cell survival, as indicated by the higher expression of IL-35 and the T-cell maturation arrest observed in PLWH. This profile was not observed in PLWH with severe immunodeficiency, highlighting the need for differentiated care in the broader PLWH population.

Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state

T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor Tcell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature Tcells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases.

Advancing Diagnostic Accuracy and Quality of Patient Care Through the Implementation of a Flow Cytometry Quality Assurance Program

Abstract Introduction/Objective Flow cytometry immunophenotypic analysis plays an important role in the diagnosis, classification and disease monitoring of hematological neoplasms. However, interpretation of flow cytometry testing can be challenging, especially when using highly complex antibody panels. Thus exploring ways to improve diagnostic accuracy and in turn improving quality of patient care is needed. Methods/Case Report A flow cytometry quality assurance (QA) program was developed. Cases from various complex flow cytometry panels were randomly selected and cross-reviewed by a second pathologist on a daily basis. The outcomes of the QA review were categorized into three groups: complete agreement, minor discrepancy and major discrepancy. Each discrepancy, once identified, underwent a process of documentation, discussion and resolution. The reports were then modified in a timely manner and the clinical teams were notified of the changes. Recurrent issues and common pitfalls were reviewed and discussed at a weekly QA meeting. Here we summarize our 3-years’ experience with this program. Results (if a Case Study enter NA) In total, 6,166 cases were evaluated by the QA program; 6,028 (97.7%) cases showed complete concordance, 120 (2.0%) cases showed minor discrepancies and 18 (0.3%) cases showed major discrepancies. Antibody panels designed to evaluate mature and immature T-cell abnormalities showed the highest rate of discrepancy, 2.8%, whereas panels designed for evaluation of myelodysplastic syndromes showed the lowest discrepancy rate, 1.7%. When analyzing the trends of concordance and discrepancy over time, we found a statistically significant decrease in discrepancies over time, from 4% at the beginning of the QA program to 1.5% in the most recent time interval. Conclusion The overall concordance rate was 97.7%. The remaining 2.3% cases showed discrepancies that required a correction, underscoring the value and necessity of having a QA program. The overall discrepancy rates exhibited a gradual decline over time, indicative of the positive impact of the QA program on enhancing diagnostic competency and accuracy over time.

ALK-positive Anaplastic Large Cell Lymphoma Involving the Spinal Cord

Abstract Introduction/Objective ALK-positive anaplastic large cell lymphoma (ALCL) is a mature T-cell lymphoma that accounts for approximately 3% of non-Hodgkin lymphoma cases in the adult population. Lymph node involvement is most commonly seen, followed by extra-nodal involvement of the skin, soft tissue, and bone. Central nervous system involvement is rare at the time of diagnosis. This case study features a patient with systemic ALK-positive ALCL involving multiple nodal and extra-nodal sites, most notably the spinal cord. Methods/Case Report A 22-year-old female presented to the hospital with worsening back pain accompanied by neurological symptoms. MRI scans of her spine revealed extensive patchy abnormal marrow signal with enhancement of the thoracolumbar vertebrae (T1-L2) and adjacent extension into the spinal canal (T3-T7, T10-L1, L3-S1) and paraspinal soft tissues. A laminectomy of the T5-T7 and T11-T12 levels was performed for surgical decompression, and epidural and paraspinal resection specimens were submitted. These specimens, along with an excisional axillary lymph node biopsy, demonstrated ALK-positive ALCL after comprehensive immunohistochemical studies. In-situ hybridization for EBV was negative. CHOP therapy was initiated, but treatment was complicated by Candidemia and disseminated intravascular coagulation. The patient rapidly declined and passed away less than a month after hospital admission. At autopsy, enlargement of lymph nodes, the left ovary (17.8 g), and spleen (383.6 g) were noted on gross examination. A solid, white-tan lesion (2.1 x 0.9 x 0.8 cm) was found in the left ovary. Necrosis and infiltrates of large, pleomorphic lymphoid cells with irregular nuclear contours and prominent nucleoli were seen on microscopic examination of the spinal cord and leptomeninges, vertebral bone marrow, mediastinal lymph nodes, spleen, and left ovary. Consistent with previously submitted surgical specimens, the viable neoplastic cells stained strongly positive for ALK-1, CD4, and CD30. Results (if a Case Study enter NA) NA Conclusion This case study highlights an atypical presentation of ALCL with a fatal outcome. Given the availability of effective treatment options, prompt diagnosis is crucial to improving survival outcomes. Additional research is necessary to elucidate the clinical and pathological features of ALCL. The differential for back pain is broad, but including this entity for patients with similarly insidious clinical presentations can prevent a delay in diagnosis that allows for rapid progression of disease.

Prevalence and Prognostication of CD5+ Mature T-Cell Lymphomas

Background: T-cell lymphomas (TCLs) are a group of heterogenous cancers with poor rates and duration of response. There remains a great challenge in risk stratification of these cancers. Cluster of differentiation (CD) 5 has shown prognostic implication in many subtypes of B-cell lymphoma; however, its role in TCLs is not known. Methods: We performed a single-institution retrospective analysis of newly diagnosed patients with TCL. CD5 positivity was determined based on positive results via immunohistochemistry and/or flow cytometry. We used univariate and multivariable analysis of biological factors to assess their association with survival outcomes. Results: A total of 194 patients with TCL spanning 14 subtypes were identified. CD5 positivity was noted in 63% of patients, with the highest proportion of CD5 expression in TFH TCL (93.9%), PTCL-NOS (82.9%), and ATLL (77.8%) (p = 0.00004). Older age at diagnosis (p = 0.001), stage III or IV disease (p = 0.05), and bone marrow involvement (p = 0.003) were also associated with CD5 expression. Complete response rates were numerically lower in patients with CD5+ TCL across all subtypes. OS/PFS was not statistically associated with CD5 status in the overall cohort; however there was significantly decreased OS in CD5+ TFH TCL (p = 0.04) and CD5+ ATLL (p = 0.04) patients. Conclusions: This study represents the first to examine CD5 expression as a prognostic biomarker for outcomes in TCL. The frequent expression of CD5 in the most common nodal TCL in the Western world underpins its potential as an attractive target for cellular therapies. Confirmation of these findings in a larger cohort and investigation of potential pathophysiological mechanisms explaining our observations are planned.

Microsurgical assessment of thymus vascular anatomy

BackgroundThe thymus is pivotal for immune system development by facilitating T-cell maturation. Current treatments for congenital athymia typically involve avascular transplantation of allogeneic thymic tissue. However, vascularizing an infant thymus for transplantation could offer improved outcomes, necessitating a detailed understanding of its vascular anatomy. MethodBetween June and November 2022, we conducted a feasibility study at our tertiary care university hospital, examining seven thymus glands that were surgically removed and discarded during corrective surgeries for congenital heart disease in patients aged 16 days to 17 months. ResultsAngiographic analysis revealed distinct vascular pathways in infant thymic lobes, with arteries averaging 0.5 mm and veins 0.8 mm in diameter, both showing adequate perfusion with Belzer solution. ConclusionThese findings provide critical insights into the vascular anatomy of the infant thymus, underscoring its potential for microvascular revascularization and transplantation.

Generation of ex vivo autologous hematopoietic stem cell-derived T lymphocytes for cancer immunotherapy

CD19CAR-T cell therapy demonstrated promising outcomes in relapsed/refractory B-cell malignancies. Nonetheless, the limited T-cell function and ineffective T-cell apheresis for therapeutic purposes are still concern in heavily pretreated patients. We investigated the feasibility of generating hematopoietic stem cell-derived T lymphocytes (HSC-T) for cancer immunotherapy. The patients’ autologous peripheral blood HSCs were enriched for CD34+ and CD3+ cells. The CD34+ cells were then cultured following three steps of lymphoid progenitor differentiation, T-cell differentiation, and T-cell maturation processes. HSC-T cells were successfully generated with robust fold expansion of 3735 times. After lymphoid progenitor differentiation, CD5+ and CD7+ cells remarkably increased (65–84 %) while CD34+ cells consequentially declined. The mature CD3+ cells were detected up to 40 % and 90 % on days 42 and 52, respectively. The majority of HSC-T population was naïve phenotype compared to CD3-T cells (73 % vs 34 %) and CD8:CD4 ratio was 2:1. The higher level of cytokine and cytotoxic granule secretion in HSC-T was observed after activation. HSC-T cells were assessed for clinical application and found that CD19CAR-transduced HSC-T cells demonstrated higher cytokine secretion and a trend of superior cytotoxicity against CD19+ target cells compared to control CAR-T cells. A chronic antigen stimulation assay revealed similar T-cell proliferation, stemness, and exhaustion phenotypes among CAR-T cell types. In conclusions, autologous HSC-T was feasible to generate with preserved T-cell efficacy. The HSC-T cells are potentially utilized as an alternative option for cellular immunotherapy.

Intron retention as an excellent marker for diagnosing depression and for discovering new potential pathways for drug intervention.

Peripheral inflammation is often associated with depressive disorders, and immunological biomarkers of depression remain a focus of investigation. We performed RNA-seq analysis of RNA transcripts of human peripheral blood mononuclear cells from a case-control study including subjects with self-reported depression in the pre-symptomatic state of major depressive disorder and analyzed differentially expressed genes (DEGs) and the frequency of intron retention (IR) using rMATS. Among the statistically significant DEGs identified, the 651 upregulated DEGs were particularly enriched in the term "bacterial infection and phagocytosis", whereas the 820 downregulated DEGs were enriched in the terms "antigen presentation" and "T-cell proliferation and maturation". We also analyzed 158 genes for which the IR was increased (IncIR) and 211 genes for which the IR was decreased (DecIR) in the depressed subjects. Although the Gene Ontology terms associated with IncIR and DecIR were very similar to those of the up- and downregulated genes, respectively, IR genes appeared to be particularly enriched in genes with sensor functions, with a preponderance of the term "ciliary assembly and function". The observation that IR genes specifically interact with innate immunity genes suggests that immune-related genes, as well as cilia-related genes, may be excellent markers of depression. Re-analysis of previously published RNA-seq data from patients with MDD showed that common IR genes, particularly our predicted immune- and cilia-related genes, are commonly detected in populations with different levels of depression, providing validity for using IR to detect depression. Depression was found to be associated with activation of the innate immune response and relative inactivation of T-cell signaling. The DEGs we identified reflect physiological demands that are controlled at the transcriptional level, whereas the IR results reflect a more direct mechanism for monitoring protein homeostasis. Accordingly, an alteration in IR, namely IncIR or DecIR, is a stress response, and intron-retained transcripts are sensors of the physiological state of the cytoplasm. The results demonstrate the potential of relative IR as a biomarker for the immunological stratification of depressed patients and the utility of IR for the discovery of novel pathways involved in recovery from depression.

Exploring the interplay between cannabinoids and thymic functions.

Cannabinoids, derived from the Cannabis sativa plant, have garnered increasing attention for their potential therapeutic applications in various diseases. The pharmacologically active compounds in Cannabis, such as delta-9-tetrahydrocannabinol and cannabidiol, exhibit diverse immunomodulatory properties. Although studies have explored the effects of cannabinoids on immune function, their specific interactions with the thymus, a primary immune organ critical for T-cell development and maturation, remain an intriguing area of investigation. As the thymus plays a fundamental role in shaping the immune repertoire, understanding the interplay between cannabinoids and thymic function may shed light on potential benefits or concerns associated with Cannabis-based therapies. This article aims to provide an overview of the current scientific knowledge regarding the impact of medicinal Cannabis on the thymus and its implications for disease treatment and immune health.

Distinct features of immune activation and exhaustion markers in people with perinatally acquired HIV.

The aim of this study was to characterize T-cell activation, exhaustion, maturation and Treg frequencies in individuals who acquire perinatal HIV (PHIV), in individuals who acquired HIV as adult (AHIV), and in healthy controls. This cross-sectional study included people with HIV at least 14 and younger than 40 years, HIV-RNA less than 50 copies/ml on antiretroviral therapy for at least 6 months, and HC. We assessed the expression of PD-1, TIM-3, EOMES, CD38 + DR+, maturation status by CD4 + and CD8 + T cells and the frequency of CD4 + and CD8 + Treg cells. Principal component analysis (PCA) and k-means cluster analysis investigated which combination of immunological parameters better associated with each group. Twenty-six PHIV and 18 AHIV with median ages of 26 (8.0) and 28 (6.8) years were consecutively enrolled. PHIV showed significant higher frequency of naive and lower frequency of terminal effector memory CD4 + and CD8 + T cells than AHIV. AHIV exhibited higher expression of exhaustion and activation markers. The statistical analysis returned two clusters with 94% of specificity and 88% of sensitivity identifying PHIV vs. AHIV. The nine healthy controls had a lower expression of exhaustion markers on both CD4 + and CD8 + T lymphocytes than PHIV and AHIV. These data may exclude major alterations of lymphopoiesis in PHIV, with even lower state of immune-activation and exhaustion compared with AHIV. This suggests that recent lack of virological control, may affect immune activation and exhaustion of CD4 + and CD8 + T cells.

Identification of host endotypes using peripheral blood transcriptomics in a prospective cohort of patients with endocarditis

ObjectivesHost responses to infection are a major determinant of outcome. However, the existence of different response profiles in patients with endocarditis has not been addressed. Our objective was to apply transcriptomics to identify endotypes in patients with infective endocarditis. MethodsA total of 32 patients with infective endocarditis were studied. Clinical data and blood samples were collected at diagnosis and RNA sequenced. Gene expression was used to identify two clusters (endocarditis endotype 1 [EE1] and endocarditis endotype 2 [EE2]). RNA sequencing was repeated after surgery. Transcriptionally active cell populations were identified by deconvolution. Differences between endotypes in clinical data, survival, gene expression, and molecular pathways involved were assessed. The identified endotypes were recapitulated in a cohort of COVID-19 patients. ResultsA total of 18 and 14 patients were assigned to EE1 and EE2, respectively, with no differences in clinical data. Patients assigned to EE2 showed an enrichment in genes related to T-cell maturation and a decrease in the activation of the signal transducer and activator of transcription protein family pathway, with higher counts of active T cells and lower counts of neutrophils. A total of 14 patients (nine in EE1 and five in EE2) were submitted to surgery. Surgery in EE2 patients shifted gene expression toward a EE1-like profile. In-hospital mortality was higher in EE1 (56% vs 14%, P = 0.027), with an adjusted hazard ratio of 12.987 (95% confidence interval 3.356-50). Translation of these endotypes to COVID-19 and non–COVID-19 septic patients yielded similar results in cell populations and outcome. ConclusionsGene expression reveals two endotypes in patients with acute endocarditis, with different underlying pathogenetic mechanisms, responses to surgery, and outcomes.

Immunophenotypic, genetic, and clinical characterization of adult T-cell leukemia/lymphoma: A single tertiary care center experience in the United States.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive mature T-cell neoplasm caused by human T-cell lymphotropic virus type 1 (HTLV-1). Its most common immunophenotype is CD4+/CD7-/CD25+, although unusual immunophenotypes can occur and may lead to misdiagnosis. The immunophenotypes, cytogenetics, molecular features, clinical presentations, treatment, and prognosis of 131 patients with ATLL were retrospectively studied in a large tertiary medical center in the United States. All cases showed loss of CD7 expression. While 82.4% of cases demonstrated CD4+, 17.6% exhibited unusual phenotypes, including CD4+/CD8+ (6.9%), CD4-/CD8- (2.3%), CD5- (3.1%), CD2-, and CD3-. The most common cytogenetics abnormalities included polysomy 3 (34.6%), translocation 1 (23.1%), and abnormalities found on chromosome 11 (30.8%) and chromosome 14 (26.9%). The common gene mutations identified by the next-generation sequencing study were TP53 (16.7%), TBL1XR1 (16.7%), EP300 (14.3%), and NOTCH1 (14.3%). TBL1XR1 mutation is associated with genetic instabilities. There was no significant difference between the clinical presentations of these 2 groups. Adult T-cell leukemia/lymphoma exhibits versatile immunophenotypic, cytogenetic, and molecular features. Simultaneous involvement of blood, lymph nodes, and other organs, along with hypercalcemia in a patient from an endemic area, necessitates HTLV-1 testing to avoid underdiagnosis of this dismal disease that might need aggressive chemotherapy followed by bone marrow transplant.

Ulk1 regulates T Cell Development and Response to Listeria monocytogenes Stimulation.

T cells are crucial for the normal functioning of the immune system. The development and response of these cells to foreign antigens involve many complex stages and interactions between various types of cells. However, many details of these processes are still unclear. Our research revealed a key role for a protein called ULK1, a serine/threonine protein kinase, in regulating T-cell development and function. During T-cell maturation, the absence of Ulk1 (as in Ulk1-/- mice) leads to an increase in a cell type called DN3 in the thymus. We also found a reduction in the number of T cells in peripheral immune organs, such as the spleen, in Ulk1-/- mice. In response to Listeria infection, Ulk1-/- mice have a weaker ability to clear this bacterium, and their T cells also have defects in producing cytokines. However, the absence of Ulk1 did not affect the activation or apoptosis of naïve CD4+ T cells in vitro. In a bone marrow chimeric mouse model, T cells from Ulk1-/- mice did not differ developmentally from those from control mice. Furthermore, RNA-seq revealed that Ulk1 deficiency affects the metabolic function of splenocytes and T-cell function in mice, potentially through the canonical Wnt signaling cascade and the ERK1/ERK2 signaling cascades. Overall, these results suggest that Ulk1 is essential for T-cell maturation in the thymus, the balance of peripheral T cells, and the functional response of T cells to antigens.

Genome-Wide Methylation Profiling of Peripheral T-Cell Lymphomas Identifies TRIP13 as a Critical Driver of Tumor Proliferation and Survival.

Cytosine methylation contributes to the regulation of gene expression and normal hematopoiesis in mammals. It is catalyzed by the family of DNA methyltransferases that include DNMT1, DNMT3A, and DNMT3B. Peripheral T-cell lymphomas (PTCLs) represent aggressive mature T-cell malignancies exhibiting a broad spectrum of clinical features with poor prognosis and inadequately understood molecular pathobiology. To better understand the molecular landscape and identify candidate genes involved in disease maintenance, we profiled DNA methylation and gene expression of PTCLs. We found that the methylation patterns in PTCLs are deregulated and heterogeneous but share 767 hypo- and 567 hypermethylated differentially methylated regions (DMRs) along with 231 genes up- and 91 genes downregulated in all samples, suggesting a potential association with tumor development. We further identified 39 hypomethylated promoters associated with increased gene expression in the majority of PTCLs. This putative oncogenic signature included the TRIP13 (thyroid hormone receptor interactor 13) gene whose genetic and pharmacologic inactivation inhibited the proliferation of T-cell lines by inducing G2-M arrest and apoptosis. Our data thus show that human PTCLs have a significant number of recurrent methylation alterations that may affect the expression of genes critical for proliferation whose targeting might be beneficial in anti-lymphoma treatments.

Возрастная динамика субпопуляций Т-лимфоцитов у пациентов с синдромом делеции 22q11.2 (синдромом Ди Джорджи)

Patients with the 22q11.2 deletion syndrome (DiGeorge syndrome, DDS) suffer from T-cell lymphopenia, changes in function and subpopulation of T-lymphocytes. The bibliographical data conflicts on the characteristics of T-lymphocytes in patients with DDS and their changes during physiological maturation. The purpose of this research was to follow-up patients with emphasis on the dynamics of changes in T-lymphocyte subpopulations with age. Methods used: 117 patients observed during 2013-2023 who were administered at the Allergology and Immunology Department with the G.N. Speransky City Children’s Hospital No. 9 (Moscow, Russia) with a diagnosis of DDS and who had undergone blood sampling to assess T-lymphocyte subpopulations using flow cytometry. All patients (0 to 18 y/o) were divided into 4 age groups: 0 to 2 y/o, 2 to 5 y/o, 5 to 10 y/o and 10 to 18 y/o. In parallel, the blood samples of 185 apparently healthy children of the corresponding age were examined. Results: a decrease in CD3 T-lymphocytes, CD4 T-helper cells, CD8 T-cytotoxic lymphocytes, CD4 early thymic emigrants and CD4 naive T-lymphocytes was found in all age groups (p&lt;0.05). CD8+ naive T-lymphocytes and CD8+ early thymic emigrants were reduced in all age groups, but in the 2 to 5 y/o age group their values were close to normal (p=0.072 and p=0.220, respectively). CD4+ central memory cells were elevated in all age groups (p&lt;0.001), while CD8+ central memory cells, CD4+ and CD8+ effector memory cells differed in that they had normal values in the 2 to 5 y/o age group (p=0.229, p=0.457 and p=0.140, respectively). CD4+ TEMRA were significantly increased in the 0 to 2 y/o age group (p=0.002), and in older age groups they tended to normal values. CD8+ TEMRA did not differ from the control group and did not have age-related dynamics. The T-helper subpopulations were characterized by a significant increase in the percentage of T-helper type 1, T-helper 17, T-helper 17.1 and a decrease in T-helper type 2 compared to the population of healthy blood sample donors (p=0.001), except for patients from the 2 to 5 y/o age group. T-regulatory cells in absolute amount were reduced in all age groups (p&lt;0.001), while their relative number corresponded to the norm in the 0 to 2 y/o age group (p=0.811) and decreased slightly in patients in older age groups, especially in the 2 to 5 y/o age group (p=0.030). Conclusion: the pathology of thymus development in patients with DDS leads to impaired maturation of T-lymphocytes, leading to an increase in the number of mature forms of T-lymphocytes, shifts towards the development of T-helper 1 and T-helper 17, and a decrease in T-regulatory cells. Disturbances in T-lymphocytes can cause changes (dysregulation) in subpopulations of B-cells. All these processes may underlie the progression of autoimmune and infectious complications in such patients that are increasing with aging.

Ultrasonographic Assessment of the Thymus Among Neonates Admitted in a Special Newborn Care Unit of a Medical College Hospital in Eastern India.

The thymus is essential for the maturation of T-lymphocytes, crucial for adaptive immunity. In neonates, thymic development is influenced by factors such as gestational age, birth weight, birth length, etc. Ultrasonography offers a non-invasive method to assess thymic size and morphology. However, there is limited research on thymic ultrasonography among neonates in Eastern India. This study aimed to investigate the ultra-sonographic characteristics of the thymus in neonates admitted to a Special Neonatal Care Unit (SNCU) in Eastern India and its correlation with certain clinical and anthropometric variables. Conducted from May to July 2024, this cross-sectional observational study involved 80 neonates admitted to the SNCU at the College of Medicine & Sagore Dutta Hospital. Thymic ultrasonography, using an Esaote MylabX7 ultrasound machine with a 3-11 MHz linear probe (Esaote, Genoa, Italy), measured thymic length, width, anteroposterior (AP) dimension, sagittal area, and thymic index. Clinical data, including gestational age, birth weight, birth length, and antibiotics received, were collected from medical records. Pearson's correlation coefficient and linear regression analysis were used to examine correlations and predictors of thymic dimensions. The cohort consisted of 45 boys (56%) and 35 girls (44%). The average birth weight was 2,626 grams for boys and 2,639 grams for girls. The median gestation period was 38 weeksfor both groups. Thymic measurements did not significantly differ by gender. Correlation analysis revealed significant relationships between thymic dimensions and neonatal anthropometric measurements. Birth weight showed a strong positive correlation with thymic length (r = 0.486) and width (r = 0.233). Linear regression identified birth weight as a significant predictor of the thymic index (p < 0.001), explaining 21.2% of the variance. This study provides insights into the factors associated with thymic size in neonates, highlighting the critical role of birth weight in thymic development. Future research should explore additional variables influencing thymic size and consider larger sample sizes to enhance model explanatory power and its potential role in immunity.

The fifth edition of the WHO-Classification - what is new for cutaneous lymphomas?

The recently published 5th edition of the "World Health Organization classification of hematolymphoid tumors: lymphoid neoplasms" provides a hierarchical reorganization. In general, new (definitive) entities as well as tumor-like lesions were included. Primary cutaneous B-cell lymphomas (CBCL) received a thorough review. A new class/family of cutaneous follicle center lymphomas was defined. Primary cutaneous marginal zone lymphoma is now presented as a separate entity independent from extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. In primary cutaneous T-cell lymphoma, former provisional entities were upgraded to definite entities. Sézary Syndrome was sorted into the class/family of mature T-cell and NK-cell leukemias. Additionally, a newly formed entity of primary cutaneous peripheral T-cell lymphoma, NOS was created for CTCL entities that do not fit into the already described CTCL entities. The increasing importance of genomic and molecular data has already been recognized in classifying leukemias and systemic lymphomas. However, in PCL the genomic landscape has not yet been fully described and validated. Therefore, future research is necessary to describe the genomic and molecular mechanisms underlying the disease entities more clearly. This would both meet a diagnostic need and valuably contribute to future classification schemes.