microRNAs calibrate T cell responses by regulating mTOR.

International audienc

Maturation stages of human T lymphocytes and distinguished by the differential expression of CD45 isoforms

Two approximately reciprocal populations of human peripheral blood T cells express high and low molecular mass isoforms of CD45, as identified by CD45RA and CD45R0 monoclonal antibodies (mAbs). Because these populations differ in their immunoregulatory functions, they were regarded as independent sublineages. However, changes in CD45 isoform expression occur during the differentiation of hematopoietic cells, and accompany the in vitro activation of T lymphocytes. This thesis presents evidence that immunological memory is associated with the CD45R0 phenotype in CD4 and CDS T cells. Limiting dilution analysis shows high frequencies of memory dependent (recall) responses among CD45R0, but not CD45RA T cells. In contrast, both populations respond with similar frequencies to alloantigens. The response kinetics essentially rule out immunoregulatory (suppressive) phenomena as an explanation for the poor responsiveness of CD45RA T cells to recall antigens. Expression of CD45RA determinants is therefore characteristic of unprimed T cells. Constitutively expressed, lymphokine-induced, and transfected class II antigens on a variety of cell types are used to probe the repertoire and the activation requirements of these cells. In the thymus, CD45R0 is the predominant CD45 isoform expressed. The significance of differential isoform expression by thymocytes is not understood. Experiments in a recently described chimeric organ culture system indicate that loss of CD45RA expression precedes the activation- induced death of thymocytes by apoptosis. Collectively, these findings imply that the sequential expression of CD45 isoforms marks stages in thymic and post-thymic T cell maturation. This conclusion suggests a dynamic view of the immune system that allows changes in both the phenotype and the functional program of individual cells

Condensin goes with the family but not with the flow

New work on genome-wide condensin binding highlights similarities and differences from cohesin

Antioxidant Treatment of Thymic Organ Cultures Decreases NF-κ B and TCF1(α) Transcription Factor Activities and Inhibits α β T cell Development.

Using electrophoretic mobility shift assays (EMSA), we have recently shown that nuclear extracts of 14-day mouse fetal thymocytes contain abundant NF-κ B transcription factor activity. To determine the functional role of NF-κ B in early thymocyte development, we have exposed fetal thymus organ cultures to inhibitors of NF-κ B activation, namely the antioxidants N-acetyl-L-cysteine and butylated hydroxyanisole. Both compounds caused a dose-dependent arrest of thymocyte differentiation toward α β, but not γ δ, T cells. This was associated with a profound decrease in nuclear content of NF-κ B and TCF1(α) transcription factor activity, as determined by EMSA. In contrast, NF-Y was affected less strongly, and cyclic AMP-response-element-binding protein levels remained essentially unchanged by antioxidants. To test the idea that α β T cell development is correlated with NF-κ B and TCF1(α) activity, we conducted additional experiments in a submersion culture system in which the generation of α β T cells can be manipulated. Standard submersion culture supports gamma delta but α β T cell development. Under these conditions, EMSA showed that transcription factor activities were similar to those seen in the presence of antioxidants. Importantly, when the generation of α β T cells in submersion culture was restored by elevating oxygen concentrations, there was a dramatic increase in TCF1(α) activity, and both NF-κ B and NF-Y returned to control levels. Taken together, these results strongly suggest that NF-κ B and TCF1(α), presumably in concert with other transcription factors, play an important role in the development of α β T cells

Clonal Selection in CD4 T cells: the role of TCR specificity and avidity

The ability to distinguish self from nonself is a fundamental property of the innate and adaptive immune system. For the somatically generated repertoire of T cell and B cell antigen receptors (TCR and BCR, respectively), self–nonself discrimination is primarily achieved through clonal deletion of lymphocytes expressing strongly auto-reactive receptors. Removal of such receptors from the TCR and BCR repertoires causes irreversible self-tolerance. For a T cell, this is a precarious life. During development in the thymus it must adopt a certain degree of self-reactivity in order to pass selection criteria, yet this must fall below a threshold, which would flag it to be negatively selected. This rigorous purging sees only approximately 3-5% of candidate thymocytes making it through the process. Once in the periphery, the quality of TCR signaling continues to be important and is heavily censored by extrinsic factors, which actively shape and condition both the pre-immune and antigen-responding repertoire. Although it is very clear that the signaling capacity of the TCR, whether this be towards self or nonself, is a key determinant in defining the trajectory of a T cell, the degree to which it governs these fate decisions remains ill defined. This thesis examines the relationship that exists between the T cell and its TCR throughout the life of a T cell

Blessing and curse of bioclimatic variables: a comparison of different calculation schemes and datasets for species distribution modeling within the extended Mediterranean area

Bioclimatic variables (BCVs) are the most widely used predictors within the field of species distribution modeling, but recent studies imply that BCVs alone are not sufficient to describe these limits. Unfortunately, the most popular database, WorldClim, offers only a limited selection of bioclimatological predictors; thus, other climatological datasets should be considered, and, for data consistency, the BCVs should also be derived from the respective datasets. Here, we investigate how well the BCVs are represented by different datasets for the extended Mediterranean area within the period 1970–2020, how different calculation schemes affect the representation of BCVs, and how deviations among the datasets differ regionally. We consider different calculation schemes for quarters/months, the annual mean temperature (BCV-1), and the maximum temperature of the warmest month (BCV-5). Additionally, we analyzed the effect of different temporal resolutions for BCV-1 and BCV-5. Differences resulting from different calculation schemes are presented for ERA5-Land. Selected BCVs are analyzed to show differences between WorldClim, ERA5-Land, E-OBS, and CRU. Our results show that (a) differences between the two calculation schemes for BCV-1 diminish as the temporal resolution decreases, while the differences for BCV-5 increase; (b) with respect to the definition of the respective month/quarter, intra-annual shifts induced by the calculation schemes can have substantially different effects on the BCVs; (c) all datasets represent the different BCVs similarly, but with partly large differences in some subregions; and (d) the largest differences occur when specific month/quarters are defined by precipitation. In summary, (a) since the definition of BCVs matches different calculation schemes, transparent communication of the BCVs calculation schemes is required; (b) the calculation, integration, or elimination of BCVs has to be examined carefully for each dataset, region, period, or species; and (c) the evaluated datasets provide, except in some areas, a consistent representation of BCVs within the extended Mediterranean region

The developmentally regulated expression of twisted gastrulation reveals a role for bone morphogenetic proteins in the control of T cell development

The evolutionarily conserved, secreted protein Twisted gastrulation (Tsg) modulates morphogenetic effects of decapentaplegic (dpp) and its orthologs, the bone morphogenetic proteins 2 and 4 (BMP2/4), in early Drosophila and vertebrate embryos. We have uncovered a role for Tsg at a much later stage of mammalian development, during T cell differentiation in the thymus. BMP4 is expressed by thymic stroma and inhibits the proliferation of CD4(-)CD8(-) double-negative (DN) thymocytes and their differentiation to the CD4(+)CD8(+) double-positive (DP) stage in vitro. Tsg is expressed by thymocytes and up-regulated after T cell receptor signaling at two developmental checkpoints, the transition from the DN to the DP and from the DP to the CD4(+) or CD8(+) single-positive stage. Tsg can synergize with the BMP inhibitor chordin to block the BMP4-mediated inhibition of thymocyte proliferation and differentiation. These data suggest that the developmentally regulated expression of Tsg may allow thymocytes to temporarily withdraw from inhibitory BMP signals