TCR signal strength controls thymic differentiation of iNKT cell subsets.

During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells

A pentapeptide as minimal antigenic determinant for MHC class I-restricted T lymphocytes

Peptides that are antigenic for T lymphocytes are ligands for two receptors, the class I or II glycoproteins that are encoded by genes in the major histocompatibility complex, and the idiotypic / chain T-cell antigen receptor1–9. That a peptide must bind to an MHC molecule to interact with a T-cell antigen receptor is the molecular basis of the MHC restriction of antigen-recognition by T lymphocytes10,11. In such a trimolecular interaction the amino-acid sequence of the peptide must specify the contact with both receptors: agretope residues bind to the MHC receptor and epitope residues bind to the T-cell antigen receptor12,13. From a compilation of known antigenic peptides, two algorithms have been proposed to predict antigenic sites in proteins. One algorithm uses linear motifs in the sequence14, whereas the other considers peptide conformation and predicts antigenicity for amphipathic -helices15,16. We report here that a systematic delimitation of an antigenic site precisely identifies a predicted pentapeptide motif as the minimal antigenic determinant presented by a class I MHC molecule and recognized by a cytolytic T lymphocyte clone

Lactate Regulates Metabolic and Proinflammatory Circuits in Control of T Cell Migration and Effector Functions

Licensed by the Creative Commons Attribution Licens

Binding of Superantigen Toxins into the CD28 Homodimer Interface Is Essential for Induction of Cytokine Genes That Mediate Lethal Shock

Bacterial superantigen toxins bind directly to the dimer interface of CD28, the principal co-stimulatory receptor, to induce a lethal cytokine storm, and peptides that prevent this binding can suppress superantigen lethality

Modern rhodolith-dominated carbonates at Punta Chivato, Mexico

Rhodolith-dominated carbonate environments, characterized by high abundances of free-living coralline algae, have been described globally from a wide range of Recent and fossil shallow marine settings. In the present-day warm-temperate Gulf of California, Mexico, rhodolith-dominated systems are important contributors to carbonate production. One of the most prolific rhodolith factories is located on the Punta Chivato shelf, in the central Gulf of California, where due to a lack of input of terrigenous material from the arid hinterland, carbonate content averages 79%. Punta Chivato rhodoliths thrive above the shallow euphotic zone under normal saline, warm-temperate and meso- to eutrophic conditions. A detailed sedimentologic study combined with acoustic seafloor mapping indicates the presence of extensive rhodolith-dominated facies at subtidal water depth covering an area of \u3e17 km2. Additional facies, surrounding the rhodolith-dominated facies include a fine-grained molluscan, a transitional bivalve-rhodolith and a bivalve facies. While the Punta Chivato shelf yields average abundances of 38% rhodolith-derived coralline algal components in the gravel-sized sediment fraction, the rhodolith facies itself is characterized by more than 60% coralline algal components. Other important carbonate producers at Punta Chivato include bivalves (35%), bryozoa (11%) and gastropods (8%). The present study shows that acoustic sediment mapping yields highly resolved continuous coverage of the seafloor and can distinguish modern rhodolith facies from surrounding sediment. This has important implications for quantifying rhodolith-dominated settings globally, as well as for ecological and conservation studies. © Publications Scientifiques du Muséum national d\u27Histoire naturelle, Paris

Attenuated T Cell Responses to a High-Potency Ligand In Vivo

According to this study, the strongest T cell receptor ligands in vitro do not necessarily induce the strongest T cell responses in vivo, suggesting that vaccine designers may need to reconsider their strategies

Memory Phenotype CD4 T Cells Undergoing Rapid, Nonburst-Like, Cytokine-Driven Proliferation Can Be Distinguished from Antigen-Experienced Memory Cells

Contrary to the current paradigm that nearly all memory T cells proliferate in response to antigenic stimulation, this paper shows that an important population of CD4 T lymphocytes achieves memory/effector status independent of antigenic stimulation

TCR cross-reactivity and allorecognition: new insights into the immunogenetics of allorecognition

Alloreactive T cells are core mediators of graft rejection and are a potent barrier to transplantation tolerance. It was previously unclear how T cells educated in the recipient thymus could recognize allogeneic HLA molecules. Recently it was shown that both naïve and memory CD4+ and CD8+ T cells are frequently cross-reactive against allogeneic HLA molecules and that this allorecognition exhibits exquisite peptide and HLA specificity and is dependent on both public and private specificities of the T cell receptor. In this review we highlight new insights gained into the immunogenetics of allorecognition, with particular emphasis on how viral infection and vaccination may specifically activate allo-HLA reactive T cells. We also briefly discuss the potential for virus-specific T cell infusions to produce GvHD. The progress made in understanding the molecular basis of allograft rejection will hopefully be translated into improved allograft function and/or survival, and eventually tolerance induction

Population mechanics: A mathematical framework to study T cell homeostasis

Unlike other cell types, T cells do not form spatially arranged tissues, but move independently throughout the body. Accordingly, the number of T cells in the organism does not depend on physical constraints imposed by the shape or size of specific organs. Instead, it is determined by competition for interleukins. From the perspective of classical population dynamics, competition for resources seems to be at odds with the observed high clone diversity, leading to the so-called diversity paradox. In this work we make use of population mechanics, a non-standard theoretical approach to T cell homeostasis that accounts for clone diversity as arising from competition for interleukins. The proposed models show that carrying capacities of T cell populations naturally emerge from the balance between interleukins production and consumption. These models also suggest remarkable functional differences in the maintenance of diversity in naïve and memory pools. In particular, the distribution of memory clones would be biased towards clones activated more recently, or responding to more aggressive pathogenic threats. In contrast, permanence of naïve T cell clones would be determined by their affinity for cognate antigens. From this viewpoint, positive and negative selection can be understood as mechanisms to maximize naïve T cell diversity

The Dynamics of T-Cell Receptor Repertoire Diversity Following Thymus Transplantation for DiGeorge Anomaly

T cell populations are regulated both by signals specific to the T-cell receptor (TCR) and by signals and resources, such as cytokines and space, that act independently of TCR specificity. Although it has been demonstrated that disruption of either of these pathways has a profound effect on T-cell development, we do not yet have an understanding of the dynamical interactions of these pathways in their joint shaping of the T cell repertoire. Complete DiGeorge Anomaly is a developmental abnormality that results in the failure of the thymus to develop, absence of T cells, and profound immune deficiency. After receiving thymic tissue grafts, patients suffering from DiGeorge anomaly develop T cells derived from their own precursors but matured in the donor tissue. We followed three DiGeorge patients after thymus transplantation to utilize the remarkable opportunity these subjects provide to elucidate human T-cell developmental regulation. Our goal is the determination of the respective roles of TCR-specific vs. TCR-nonspecific regulatory signals in the growth of these emerging T-cell populations. During the course of the study, we measured peripheral blood T-cell concentrations, TCRβ V gene-segment usage and CDR3-length spectratypes over two years or more for each of the subjects. We find, through statistical analysis based on a novel stochastic population-dynamic T-cell model, that the carrying capacity corresponding to TCR-specific resources is approximately 1000-fold larger than that of TCR-nonspecific resources, implying that the size of the peripheral T-cell pool at steady state is determined almost entirely by TCR-nonspecific mechanisms. Nevertheless, the diversity of the TCR repertoire depends crucially on TCR-specific regulation. The estimated strength of this TCR-specific regulation is sufficient to ensure rapid establishment of TCR repertoire diversity in the early phase of T cell population growth, and to maintain TCR repertoire diversity in the face of substantial clonal expansion-induced perturbation from the steady state