A new mechanism shapes the naïve CD8+ T cell repertoire: the selection for full diversity

During thymic T cell differentiation, TCR repertoires are shaped by negative, positive and agonist selection. In the thymus and in the periphery, repertoires are also shaped by strong inter-clonal and intra-clonal competition to survive death by neglect. Understanding the impact of these events on the T cell repertoire requires direct evaluation of TCR expression in peripheral naïve T cells. Several studies have evaluated TCR diversity, with contradictory results. Some of these studies had intrinsic technical limitations since they used material obtained from T cell pools, preventing the direct evaluation of clone sizes. Indeed with these approaches, identical TCRs may correspond to different cells expressing the same receptor, or to several amplicons from the same T cell. We here overcame this limitation by evaluating TCRB expression in individual naïve CD8+ T cells. Of the 2269 Tcrb sequences we obtained from 13 mice, 99% were unique. Mathematical analysis of this data showed that the average number of naïve peripheral CD8+ T cells expressing the same TCRB is 1.1 cell. Since TCRA co-expression studies could only increase repertoire diversity, these results reveal that the number of naïve T cells with unique TCRs approaches the number of naïve cells. Since thymocytes undergo multiple rounds of divisions after TCRB rearrangement; and 3–5% of thymocytes survive thymic selection events; the number of cells expressing the same TCRB was expected to be much higher. Thus, these results suggest a new repertoire selection mechanism, which strongly selects for full TCRB diversity

Composite bottlebrush mechanics: ?-internexin fine-tunes neurofilament network properties

Neuronal cytoplasmic intermediate filaments are principal structural and mechanical elements of the axon. Their expression during embryonic development follows a differential pattern, while their unregulated expression is correlated to neurodegenerative diseases. The largest neurofilament proteins of medium (NF-M) and high molecular weight (NF-H) were shown to modulate the axonal architecture and inter-filament spacing. However, the individual roles of the remaining α-internexin (α-Inx) and neurofilament of low molecular weight (NF-L) proteins in composite filaments remained elusive. In contrast to previous predictions, we show that when co-assembled with NF-M, the shortest and the least charged α-Inx protein increases inter-filament spacing. These findings suggest a novel structural explanation for the expression pattern of neurofilament proteins during embryonic development. We explain our results by an analysis of ionic cross-links between the disordered polyampholytic C-terminal tails and suggest that a collapsed conformation of the α-Inx tail domain interferes with tail cross-linking near the filament backbone

Different initiation of pre-TCR and gamma delta TCR signalling

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Thymic selection revisited : how essential is it?

Intrathymic T cell development represents one of the best studied paradigms of mammalian development. Lymphoid committed precursors enter the thymus and the Notch1 receptor plays an essential role in committing them to the T cell lineages. The pre-T cell receptor (TCR), as an autonomous cell signaling receptor, commits cells to the \u3b1\u3b2 lineage while its rival, the \u3b3\u3b4TCR, is involved in generating the \u3b3\u3b4 lineage of T cells. Positive and negative selection of immature \u3b1\u3b2TCR-expressing cells are essential mechanisms for generating mature T cells, committing them to the CD4 and CD8 lineages and avoiding autoimmunity. Additional lineages of \u3b1\u3b2T cells, such as the natural killer T cell lineage and the CD25+ regulatory T cell lineage, are formed when the \u3b1\u3b2TCR encounters specific ligands in suitable microenvironments. Thus, positive selection and receptor-instructed lineage commitment represent a hallmark of the thymus. Ectopically expressed organ-specific antigens contribute to thymic self-nonself discrimination, which represents an essential feature for the evolutionary fitness of mammalian species