A revival of the B cell paradigm for rheumatoid arthritis pathogenesis?

Dominant paradigms for the understanding of rheumatoid arthritis (RA) pathogenesis have changed over the years. A predominant role of B lymphocytes, and perhaps of the rheumatoid factor they produced, was initially invoked. In more recent years, recognition of antigens in the joint by T cells sparking an inflammatory cascade has been a more favored interpretation. Here, we re-examine some of the arguments that underpin this proposed role of joint T cells, in light of recent results from transgenic mice in which a self-reactive T-cell receptor provokes disease, but from outside the joint and indirectly via B lymphocytes and immunoglobulins

Abell 2384: the galaxy population of a cluster post-merger

We combine multi-object spectroscopy from the 2dF and EFOSC2 spectrographs with optical imaging of the inner 30'x30' of A2384 taken with the ESO Wide Field Imager. We carry out a kinematical analysis using the EMMIX algorithm and biweight statistics. We address the possible presence of cluster substructures with the Dressler-Shectman test. Cluster galaxies are investigated with respect to [OII] and H{\alpha} equivalent width. Galaxies covered by our optical imaging observations are additionally analysed in terms of colour, star formation rate and morphological descriptors such as Gini coefficient and M20 index. We study cluster galaxy properties as a function of clustercentric distance and investigate the distribution of various galaxy types in colour-magnitude and physical space. The Dressler-Shectman test reveals a substructure in the east of the 2dF field-of-view. We determine the mass ratio between the northern and southern subcluster to be 1.6:1. In accordance with other cluster studies, we find that a large fraction of the disk galaxies close to the cluster core show no detectable star formation. Probably these are systems which are quenched due to ram-pressure stripping. The sample of quenched disks populates the transition area between the blue cloud and the red sequence in colour-magnitude space. We also find a population of morphologically distorted galaxies in the central cluster region. The substructure in the east of A2384 might be a group of galaxies falling onto the main cluster. We speculate that our sample of quenched spirals represents an intermediate phase in the ram-pressure driven transformation of infalling field spirals into cluster S0s. This is motivated by their position in colour-magnitude space. The occurrence of morphologically distorted galaxies in the cluster core complies with the hypothesis of A2384 representing a post merger system.Comment: 14 pages, 18 figures, A&A accepte

TCR-based lineage tracing: no evidence for conversion of conventional into regulatory T cells in response to a natural self-antigen in pancreatic islets

Foxp3-expressing regulatory T (T reg) cells derive primarily from selection in the thymus. Yet conversion of mature conventional CD4+ T (T conv) cell lymphocytes can be achieved in several conditions, such as transforming growth factor β treatment, homeostatic expansion, or chronic exposure to low-dose antigen. Such conversion might provide a means to generate peripheral tolerance by “converting” potentially damaging T cells that react to self-antigens. We tested this hypothesis in mice transgenic for the BDC2.5 T cell receptor (TCR), which is representative of a diabetogenic specificity that is naturally present in NOD mice and reactive against a pancreatic self-antigen. In the thymus, before any exposure to antigen, clonotype-positive T reg and T conv cells express a second TCRα chain derived from endogenous loci. High-throughput single-cell sequencing of secondary TCRs of the Vα2 family showed their joining CDR3α regions to be very different in T reg and T conv cell thymocytes. These specific CDR3α motifs, thus, provided a “tag” with which to test the actual impact of T conv to T reg cell conversion in response to peripheral self-antigen; should the autoreactive clonotypic TCR induce T conv to T reg cell conversion upon encounter of cognate antigen in the pancreas or draining lymph node, one would expect to detect tag CDR3α motifs from T conv cells in the T reg cell populations. Sequencing large numbers of peripheral BDC+Vα2+ cells showed that little to no conversion occurs in response to this pancreatic autoantigen

The AKT–mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells

CD4+Foxp3+ regulatory T (T reg) cells play an essential role in maintaining immunological tolerance via their suppressive function on conventional CD4+ T (Tconv) cells. Repertoire studies suggest that distinct T cell receptor signaling pathways lead to T reg differentiation, but the signals that regulate T reg specification are largely unknown. We identify AKT as a strong repressor of entry into the T reg phenotype in vitro and in vivo. A constitutively active allele of AKT substantially diminished TGF-β–induced Foxp3 expression in a kinase-dependent manner and via a rapamycin-sensitive pathway, implicating the AKT–mammalian target of rapamycin axis. The observed impairment in Foxp3 induction was part of a broad dampening of the typical T reg transcriptional signature. Expression of active AKT at a stage before Foxp3 turn on during normal T reg differentiation in the thymus selectively impaired differentiation of CD4+Foxp3+ cells without any alteration in the positive selection of Tconv. Activated AKT, in contrast, did not affect established Foxp3 expression in T reg cells. These results place AKT at a nexus of signaling pathways whose proper activation has a strong and broad impact on the onset of T reg specification

Aire's Partners in the Molecular Control of Immunological Tolerance

SummaryAire induces the expression of a battery of peripheral-tissue self-antigens (PTAs) in thymic stromal cells, promoting the clonal deletion of differentiating T cells that recognize them. Just how Aire targets and induces PTA transcripts remains largely undefined. Screening via Aire-targeted coimmunoprecipitation followed by mass spectrometry, and validating by multiple RNAi-mediated knockdown approaches, we identified a large set of proteins that associate with Aire. They fall into four major functional classes: nuclear transport, chromatin binding/structure, transcription and pre-mRNA processing. One set of Aire interactions centered on DNA protein kinase and a group of proteins it partners with to resolve DNA double-stranded breaks or promote transcriptional elongation. Another set of interactions was focused on the pre-mRNA splicing and maturation machinery, potentially explaining the markedly more effective processing of PTA transcripts in the presence of Aire. These findings suggest a model to explain Aire's widespread targeting and induction of weakly transcribed chromatin regions.PaperCli

Imputing gene expression from optimally reduced probe sets

Measuring complete gene expression profiles for a large number of experiments is costly. We propose an approach in which a small subset of probes is selected based on a preliminary set of full expression profiles. In subsequent experiments, only the subset is measured, and the missing values are imputed. We develop several algorithms to simultaneously select probes and impute missing values, and demonstrate that these probe selection for imputation (PSI) algorithms can successfully reconstruct missing gene expression values in a wide variety of applications, as evaluated using multiple metrics of biological importance. We analyze the performance of PSI methods under varying conditions, provide guidelines for choosing the optimal method based on the experimental setting, and indicate how to estimate imputation accuracy. Finally, we apply our approach to a large-scale study of immune system variation

Number of T Reg Cells That Differentiate Does Not Increase upon Encounter of Agonist Ligand on Thymic Epithelial Cells

It has been reported that the differentiation of CD4+CD25+ regulatory T cells (T reg cells) can be induced by agonist peptide/major histocompatibility complex ligands in the thymus. Exploiting a transgenic mouse line wherein expression of a particular T cell epitope can be controlled temporally and quantitatively, we found that diversion of differentiating thymocytes into the FoxP3 T reg cell pathway by this agonist ligand was essentially nonexistent. However, CD4+CD25+ thymocytes were much less sensitive than their CD4+CD25− companions, by two to three orders of magnitude, to agonist-induced clonal deletion, such that their proportion increased, giving the false impression of induced differentiation. To account for these and prior observations, one can propose that differentiation along the CD4+CD25+ pathway is induced by cues other than recognition of self-agonist cues, which are poorly read by thymocytes, whose T cell receptors are conducive to selection toward the conventional CD4+CD25− lineage. Thus, selective survival, rather than induced differentiation, may explain the apparent enrichment observed here and in previous studies

Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2

Regulatory T (T reg) cells control progression to autoimmune diabetes in the BDC2.5/NOD mouse model by reining in natural killer (NK) cells that infiltrate the pancreatic islets, inhibiting both their proliferation and production of diabetogenic interferon-γ. In this study, we have explored the molecular mechanisms underlying this NK–T reg cell axis, following leads from a kinetic exploration of gene expression changes early after punctual perturbation of T reg cells in BDC2.5/NOD mice. Results from gene signature analyses, quantification of STAT5 phosphorylation levels, cytokine neutralization experiments, cytokine supplementation studies, and evaluations of intracellular cytokine levels collectively argue for a scenario in which T reg cells regulate NK cell functions by controlling the bioavailability of limiting amounts of IL-2 in the islets, generated mainly by infiltrating CD4+ T cells. This scenario represents a previously unappreciated intertwining of the innate and adaptive immune systems: CD4+ T cells priming NK cells to provoke a destructive T effector cell response. Our findings highlight the need to consider potential effects on NK cells when designing therapeutic strategies based on manipulation of IL-2 levels or targets