Stepwise Development of MAIT Cells in Mouse and Human

Mucosal-associated invariant T (MAIT) cells display two evolutionarily conserved features: an invariant T cell receptor (TCR)α (iTCRα) chain and restriction by the nonpolymorphic class Ib major histocompatibility complex (MHC) molecule, MHC-related molecule 1 (MR1). MR1 expression on thymus epithelial cells is not necessary for MAIT cell development but their accumulation in the gut requires MR1 expressing B cells and commensal flora. MAIT cell development is poorly known, as these cells have not been found in the thymus so far. Herein, complementary human and mouse experiments using an anti-humanVα7.2 antibody and MAIT cell-specific iTCRα and TCRβ transgenic mice in different genetic backgrounds show that MAIT cell development is a stepwise process, with an intra-thymic selection followed by peripheral expansion. Mouse MAIT cells are selected in an MR1-dependent manner both in fetal thymic organ culture and in double iTCRα and TCRβ transgenic RAG knockout mice. In the latter mice, MAIT cells do not expand in the periphery unless B cells are added back by adoptive transfer, showing that B cells are not required for the initial thymic selection step but for the peripheral accumulation. In humans, contrary to natural killer T (NKT) cells, MAIT cells display a naïve phenotype in the thymus as well as in cord blood where they are in low numbers. After birth, MAIT cells acquire a memory phenotype and expand dramatically, up to 1%–4% of blood T cells. Finally, in contrast with NKT cells, human MAIT cell development is independent of the molecular adaptor SAP. Interestingly, mouse MAIT cells display a naïve phenotype and do not express the ZBTB16 transcription factor, which, in contrast, is expressed by NKT cells and the memory human MAIT cells found in the periphery after birth. In conclusion, MAIT cells are selected by MR1 in the thymus on a non-B non-T hematopoietic cell, and acquire a memory phenotype and expand in the periphery in a process dependent both upon B cells and the bacterial flora. Thus, their development follows a unique pattern at the crossroad of NKT and γδ T cells

Identification des cellules présentatrices d'antigène qui sélectionnent/induisent les cellules MAIT et T régulatrices dans le thymus

PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Revisione delle industrie litiche di grotta Spagnoli B (Foggia)

Gli Autori presentano i risultati preliminari della revisione delle industrie litiche di Grotta Spagnoli B, oggetto di ricerche negli anni 1969-79 da parte di Mara Guerri. In questo studio viene preso in considerazione l’intero insieme, in precedenza edito solo parzialmente. Se ne propone l’attribuzione crono-culturale in una fase iniziale del MIS 4

An atlas for clinical target volume definition, including elective nodal irradiation in definitive radiotherapy of biliary cancer

Radiotherapy (RT) is a treatment option for advanced biliary tract cancer (BTC), often combined with sequential and/or concurrent chemotherapy. The use of modern RT techniques requires accurate clinical target volume (CTV) definition and delineation. However, guidelines for CTV delineation in BTC are lacking. Therefore, the aim of this study was to propose a computer tomography (CT) atlas for CTV definition of BTC. We previously proposed guidelines to define the nodal CTV (CTV-N) in BTC. In this study, based on a literature analysis, we defined the margins to be added to the gross tumor volume (GTV; subclinical and microscopic disease) to define the primary tumor CTV (CTV-T). An abdominal contrast enhanced planning CT scan was performed on three different patients with unresectable intrahepatic cholangiocarcinoma (CC), extrahepatic CC and gallbladder cancer. The GTV and anatomical reference structures were outlined on CT images. Then, based on our guidelines, the CTV-T and CTV-N were delineated and merged to define the final CTV in the three patients. An atlas, showing the defined CTV, was generated from the reference CT images to illustrate the CTV for intra-hepatic CC, extra-hepatic CC and gallbladder cancer. This atlas can be used as an aid for CTV definition in patients with BTC treated with modern RT techniques

Genetic landscape of T cells identifies synthetic lethality for T-ALL

O'Meara et al. utilize a panel of zebrafish mutants to perform a whole organism genetic interaction screen, examining the network regulating T cell differentiation. The authors use a T cell acute lymphoblastic leukemia (T-ALL) model to integrate the effects of small molecule inhibitors of the T cell differentiation pathway and establish a combination therapy for T-ALL in juvenile zebrafish. To capture the global gene network regulating the differentiation of immature T cells in an unbiased manner, large-scale forward genetic screens in zebrafish were conducted and combined with genetic interaction analysis. After ENU mutagenesis, genetic lesions associated with failure of T cell development were identified by meiotic recombination mapping, positional cloning, and whole genome sequencing. Recessive genetic variants in 33 genes were identified and confirmed as causative by additional experiments. The mutations affected T cell development but did not perturb the development of an unrelated cell type, growth hormone-expressing somatotrophs, providing an important measure of cell-type specificity of the genetic variants. The structure of the genetic network encompassing the identified components was established by a subsequent genetic interaction analysis, which identified many instances of positive (alleviating) and negative (synthetic) genetic interactions. Several examples of synthetic lethality were subsequently phenocopied using combinations of small molecule inhibitors. These drugs not only interfered with normal T cell development, but also elicited remission in a model of T cell acute lymphoblastic leukaemia. Our findings illustrate how genetic interaction data obtained in the context of entire organisms can be exploited for targeted interference with specific cell types and their malignant derivatives

Early impairment of the full-field photopic negative response in patients with Stargardt disease and pathogenic variants of the ABCA4 gene

BACKGROUND: To study the photopic negative response of the full-field photopic ERG in Stargardt patients with pathogenic variants in the ABCA4 gene. METHODS: A retrospective analysis of 35 Stargardt patients with ABCA4 gene pathogenic variants, compared to normal age matched controls. Patients were clinically followed at the Ophthalmology Department of Fondazione Policlinico Universitario A. Gemelli/Universit\ue0 Cattolica del Sacro Cuore - Rome, Italy. RESULTS: The photopic negative response of the full-field photopic ERG was compromised in most Stargardt patients. In the presence of a normal B-wave, the amplitude ratio between the photopic negative response and the B-wave displayed a 97% accuracy in detecting diseased eyes (ROC curves). CONCLUSIONS: In Stargardt patients with ABCA4 pathogenic mutations, the photopic negative response of the full-field photopic ERG is a very sensitive disease read-out. Its inclusion in standard ERG analysis would be a no-cost addition of practical consequence in the follow-up of Stargardt disease. The early impairment of the photopic negative response suggests that inner retinal function might be affected in Stargardt disease earlier than previously acknowledged

Medulla formation is controlled by autoreactive CD4⁺ thymocytes.

<p>(A) Thymic sections from <i>Rag2</i>^−/− mice and <i>Marilyn:Rag2</i>^−/− females or males were stained with antibodies against K8 and K14: m, medulla. The graph shows quantifications of medullary areas: symbols represent individual confocal images; lines represent medians; data from 3 experiments, each with 2–3 mice per group. (B) The graph shows numbers per thymus of CD45⁻EpCAM⁺Ly51^−/lo mTECs and CD45⁻EpCAM⁺Ly51⁺ cTECs in <i>Marilyn:Rag2</i>^−/− females and males: means and SD from 3 experiments. (C) Representative FACS profiles are shown for Ly51 expression by CD45⁻EpCAM⁺ TECs from WT→WT and mixed H-Y+WT→WT (1∶1 ratio) chimeras. Graphs show percentages of CD45⁻EpCAM⁺Ly51^−/lo mTECs and numbers per thymus of CD45⁻EpCAM⁺Ly51^−/lo mTECs and CD45⁻EpCAM⁺Ly51⁺ cTECs for chimeras prepared with the indicated H-Y∶WT BM ratio: means and SD derived from 3 measurements; significance relative to WT→WT chimeras (0∶1 ratio). (D) Representative FACS profiles are shown for Ki67 expression by CD45⁻EpCAM⁺Ly51^−/lo mTECs from WT→WT and mixed H-Y+WT→WT (1∶1 ratio) chimeras. Graphs show percentages and numbers per thymus of Ki67⁺ mTECs for chimeras prepared with the indicated H-Y∶WT BM ratio: means and SD from 3 measurements; significance relative to WT→WT chimeras (0∶1 ratio).</p