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T‐cell acute lymphoblastic leukaemia (T‐ALL) is a heterogeneous malignant disease with high relapse and mortality rates. To characterise the multiomics features of T‐ALL, we conducted integrative analyses using single‐cell RNA, TCR and chromatin accessibility sequencing on pre‐ and post‐treatment peripheral blood and bone marrow samples of the same patients. We found that there is transcriptional rewiring of gene regulatory networks in T‐ALL cells. Some transcription factors, such as TCF3 and KLF3, showed differences in activity and expression levels between T‐ALL and normal T cells and were associated with the prognosis of T‐ALL patients. Furthermore, we identified multiple malignant TCR clonotypes among the T‐ALL cells, where the clonotypes consisted of distinct combinations of the same TCR α and β chain per patient. The T‐ALL cells displayed clonotype‐specific immature thymocyte cellular characteristics and response to chemotherapy. Remarkably, T‐ALL cells with an orphan TCRβ chain displayed the strongest stemness and resistance to chemotherapy. Our study provided transcriptome and epigenome characterisation of T‐ALL cells categorised by TCR clonotypes, which may be helpful for the development of novel predictive markers to evaluate treatment effectiveness for T‐ALL. Delineation of rewired regulatory networks and TCR clonotype‐specific heterogeneity in T‐ALL cells by single‐cell multiomics, providing critical insights for potential therapeutic targets, disease stratification method and prognosis predictor for T‐ALL.

Background : Common carotid artery (CCA) ultrasound with measurement of intima-media thickness (IMT) is a safe and noninvasive technique for assessing subclinical atherosclerosis and determining cardiovascular risks. Moreover, the pattern of wall thickening in the brachial artery (BA) is rather diffuse compared to the carotid artery and may be a more sensitive indicator of long-term systemic exposure to risk factors. Therefore noninvasive evaluation of mechanical parameters changes of both arteries has gained the attention of researchers. Objectives : The aim of this study was to compare different edge detection techniques with speckle reducing anisotropic diffusion (SRAD) de-noising filter in ultrasound images of both arteries. Patients and Methods : In a cross-sectional design, an examination was performed on ten men with mean age of 40 ± 5 years from September 2012 to March 2013 through random sampling. An ultrasonic examination of the left CCA and BA was performed. The program was designed in the MATLAB software to extract consecutive images in JPEG format from the AVI. Another program was designed in the MATLAB software to apply regions of interest (ROI) on the IMT of the posterior wall of common carotid and brachial arteries. Next, different edge detections and SRAD filter were applied to the ROI, separately. Finally, the program measured mean-squared error (MSE) and peak signal to noise ratio (PSNR). Results : The lowest values of MSE and highest values of PSNR were achieved by Canny edge detection with de-noising SRAD filter for IMT of left CCA and BA in 90 frames. Conclusions : Based on the result, by measuring the MSE and PSNR, this study showed Canny edge detection with SRAD filter is better than other edge detections in terms of speckle suppression and details preservation in CCA and BA ultrasound images.

The non-obese diabetic (NOD) mouse spontaneously develops T-cell-dependent autoimmune diabetes. This mouse strain has a number of immune dysfunctions related to T-cell development but so far there are no available data on the proliferation of NOD immature thymocytes. We therefore studied the thymocyte proliferation in the NOD mouse in discrete stages of T-cell development. We depleted thymocytes in vivo and analysed thymocyte proliferation during the thymus recovery from depletion. We used co-segregation analysis and quantitative loci trait analysis to investigate the genetic control of proliferation impairments in NOD thymocytes. Immature thymocytes of female NOD mice proliferate with a relatively low rate compared to non-autoimmune C57Bl/6 mice. This aberrant proliferation was most pronounced in CD4-/lo CD8+ cells differentiating from the CD4-CD8- to the CD4+CD8+ stage. A genetic mapping study using an F2 intercross between the NOD and the C57BL/6 strains showed that a major locus controlling this trait is linked to the insulin-dependent diabetes susceptibility locus Idd6. Our results suggest that impairment of proliferation of immature thymocytes is one possible mechanism through which the Idd6 locus contributes to the pathogenesis of diabetes.

Involution of the thymus is accompanied by a decline in the number of thymic epithelial cells (TECs) and a severely restricted peripheral repertoire of T-cell specificities. TECs are essential for T-cell differentiation; they originate from a bipotent progenitor that gives rise to cells of cortical (cTEC) and medullary (mTEC) phenotypes, via compartment-specific progenitors. Upon acute selective near-total ablation during embryogenesis, regeneration of TECs fails, suggesting that losses from the pool of TEC progenitors are not compensated. However, it is unclear whether this is also true for the compartment-specific progenitors. The decline of cTECs is a prominent feature of thymic involution. Because cTECs support early stages of T-cell development and hence determine the overall lymphopoietic capacity of the thymus, it is possible that the lack of sustained regenerative capacity of cTEC progenitor cells underlies the process of thymic involution. Here, we examine this hypothesis by cell-type–specific conditional ablation of cTECs. Expression of the human diphtheria toxin receptor (hDTR) gene under the regulatory influence of the chemokine receptor Ccx-ckr1 gene renders cTECs sensitive to the cytotoxic effects of diphtheria toxin (DT). As expected, DT treatment of preadolescent and adult mice led to a dramatic loss of cTECs, accompanied by a rapid demise of immature thymocytes. Unexpectedly, however, the cTEC compartment regenerated after cessation of treatment, accompanied by the restoration of T-cell development. These findings provide the basis for the development of targeted interventions unlocking the latent regenerative potential of cTECs to counter thymic involution.

Invariant natural killer T (iNKT) cells constitute a subpopulation of T cells that recognize glycolipids presented by CD1d molecules. They are characterized by their prompt production of interleukin-4 (IL-4) and interferon-gamma (IFN-gamma), which enables them to modulate diverse immune responses. Recently, we enlarged this concept by identifying a distinct IL-17-producing iNKT cell subset, named iNKT17 cells. The mechanisms leading to the acquisition of this new iNKT cell activity are unknown. Herein we show that IL-17-producing iNKT cells are already present in the thymus, predominantly among a subset regarded so far as an immature stage of thymic iNKT cell development, the CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) cells. Using EGFP reporter mice, we demonstrate that the transcription factor ROR-gammat is critical for the thymic differentiation of this subset because only ROR-gammat(pos) iNKT cells are capable of massively secreting IL-17. Moreover, IL-17-producing CD1d tetramer(pos)CD44(pos)NK1.1(neg)CD4(neg) thymic iNKT cells have reached a mature differentiation stage because they fail to generate other cell subsets in fetal thymic organ culture. Conversely, thymic ROR-gammat(neg) iNKT cell precursors give rise to progeny, but acquire neither ROR-gammat expression nor the ability to secrete IL-17. In conclusion, our findings demonstrate an alternative thymic pathway leading to the development of iNKT17 cells that requires ROR-gammat expression.

T cell receptor/CD3 ligation induces apoptosis in semimature CD4+8- HSA+ thymocytes, and this helps establish immunological tolerance and constitutes one of the safeguards against autoimmune disease. We analyzed several knockout and transgenic mouse lines and found that T cell receptor/CD3-ligation-induced killing of semimature thymocytes occurred independently of Fas and \"death receptor\" signaling in general but required the proapoptotic BH3-only protein Bim and could be inhibited by Bcl-2. Loss of Apaf-1 or caspase-9, which act downstream of the Bcl-2 family protein family, provided only minor protection, indicating that the \"apoptosome\" functions as an amplifier rather than as an essential initiator of this death program. These results reveal the mechanisms of apoptosis in negative selection of semimature thymocytes and have implications for immunological tolerance and autoimmunity.

The T-cell receptor (TCR) β chain is instrumental in the progression of thymocyte differentiation from the CD4-CD8-to the CD4+CD8+stage. This differentiation step may involve cell surface expression of novel CD3-TCR complexes. To facilitate biochemical characterization of these complexes, we established cell lines from thymic lymphomas originating from mice carrying a mutation in the p53 gene on the one hand and a mutation in TCR-α, TCR-β, or the recombination activating gene 1 (RAG-1) on the other hand. The cell lines were CD4+CD8+and appeared to be monoclonal. A cell line derived from a RAG-1 x p53 double mutant thymic lymphoma expressed low levels of CD3-ε, -γ, and -δ on the surface. TCR-α x p53 double mutant cell lines were found to express complexes consisting of TCR-β chains associated with CD3-ε, -γ, and -δ chains and CD3-ζζ dimers. These cell lines will be useful tools to study the molecular structure and signal transducing properties of partial CD3-TCR complexes expressed on the surface of immature thymocytes.

The T-cell receptor, which recognizes antigen plus a product of the major histocompatibility complex, has been postulated to drive T-cell maturation in the thymus by engaging major histocompatibility complex proteins expressed on thymic stromal cells. We tested this idea by injecting neonatal animals with an anti-receptor antibody, KJ16, that binds to about 20% of T cells and is capable of blocking receptor function. In the presence of this antibody, mature T cells bearing the KJ16 epitope failed to develop. On the other hand, although the antibody could be shown to bind to receptors on cortical thymocytes, it did not prevent the rapid expansion or survival of the bulk of the KJ16+ cells in this population. These results are consistent with the hypothesis that most cortical thymocytes arise by a receptor-independent mechanism and that only a small proportion of these cells mature by a process dependent on receptor--major histocompatibility complex interactions.