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

Genome-Wide Analyses of Exonic Copy Number Variants in a Family-Based Study Point to Novel Autism Susceptibility Genes

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11–q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3×10−5). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3×10−4). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3×10−39), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts

Rotating Stars in Relativity

Rotating relativistic stars have been studied extensively in recent years, both theoretically and observationally, because of the information one could obtain about the equation of state of matter at extremely high densities and because they are considered to be promising sources of gravitational waves. The latest theoretical understanding of rotating stars in relativity is reviewed in this updated article. The sections on the equilibrium properties and on the nonaxisymmetric instabilities in f-modes and r-modes have been updated and several new sections have been added on analytic solutions for the exterior spacetime, rotating stars in LMXBs, rotating strange stars, and on rotating stars in numerical relativity.Comment: 101 pages, 18 figures. The full online-readable version of this article, including several animations, will be published in Living Reviews in Relativity at http://www.livingreviews.org

Subtle effects on myelin basic protein-specific T cell responses can lead to a major reduction in disease susceptibility in experimental allergic encephalomyelitis

The presence of potentially autoreactive T cells is a necessary, but not sufficient, condition for the development of autoimmune disease. However, the relationship between T cell response and susceptibility to disease is not straightforward. In this report, we use experimental allergic encephalomyelitis as a model to demonstrate that subtle alterations of the T cell response to an encephalitogenic epitope are sufficient to cause a dramatic decrease in disease susceptibility. Transgenic expression of a fusion protein of hen egg lysozyme and an encephalitogenic peptide of myelin basic protein (MBP) residues 84-105, coexpressed with MHC class H, causes profound tolerance to hen egg lysozyme, while maintaining a near normal response to MBP. Detailed analysis of the T cell repertoire of transgenic animals using a panel of T cell hybridomas revealed a highly selective loss of one minor component of the response to the MBP84-104 region. Despite this, transgenic animals were highly resistant to experimental allergic encephalomyelitis induction with the MBP peptide, indicating that minor changes to the T cell repertoire may result in major alterations in disease susceptibility. Possible reasons for this are discussed.link_to_subscribed_fulltex

Class I cross-restricted T cells reveal low responder allele due to processing of viral antigen.

Cytotoxic T lymphocytes (CTL) recognize protein antigens which have been processed by the target cell and then presented in association with the relevant class I molecule of the major histocompatibility complex (MHC). Short synthetic peptides, which are able to associate directly with target cells, may substitute for these processed fragments in stimulating antigen-specific CTL responses. Using this approach, a dominant HLA-A2-restricted epitope has previously been mapped to residues 58-68 of influenza A virus matrix protein. Here we report HLA-A2-restricted CTL which are also able to recognize this short synthetic peptide in association with HLA-Aw69, but which fail to recognize HLA-Aw69 expressing cells infected with influenza A virus. Furthermore, individuals possessing HLA-Aw69 who respond to influenza A virus, do not respond to M58-68. These results imply that the low response to this epitope on infection of HLA-Aw69 individuals with influenza A is due to failure of the naturally processed product of matrix protein to associate with Aw69

Transforming growth factor beta stimulation of colorectal cancer cell lines: type II receptor bypass and changes in adhesion molecule expression.

The type II transforming growth factor (TGF)-beta receptor gene (TGFBR2) is often mutated in nucleotide repeat sequences in colorectal cancers that are replication error positive (RER+). These mutations are thought to be selected for escape from growth inhibition by TGF-beta rather than representing bystander events because of an increased mutation rate. We investigated the role of TGFBR2 mutations in 12 colorectal cancer cell lines. Six of these were RER+, and these were shown to have homozygous TGFBR2 mutations. All cell lines then were tested for changes in proliferation in response to TGF-beta stimulation. Despite homozygous mutation of the type II TGF-beta receptor, two RER+ cell lines, Lovo and SW48, showed statistically significant growth inhibition when stimulated by TGF-beta1 in serum-free conditions. This shows that the type II TGF-beta receptor can be bypassed in certain cases to maintain growth inhibition. We next investigated whether there was any alternative mode through which TGFBR2 mutation may give a selective advantage, such as a change in adhesion molecule expression. All cell lines were stimulated with TGF-beta1 and adhesion molecules detected by ELISA. No consistent changes were identified between the RER+ and the RER- cell lines, although changes in E-cadherin, beta-catenin, and gamma-catenin were identified in individual cell lines. We conclude that (i) type II TGF-beta receptor activity can be bypassed and thus TGFBR2 mutations in RER+ cancers may, at least sometimes, be just "bystander" events and (ii) TGF-beta can affect adhesion molecule expression so that TGFBR2 mutation may give rise to a selective advantage through an effect other escape from growth inhibition

Chondrocyte antigen expression, immune response and susceptibility to arthritis

The association of HLA-B27 with certain forms of arthritis implies a role for MHC class I-restricted T cells in the arthritic process. Our aim was to study CD8+ T cell responses towards specific antigens localized in joint tissue. Known determinants were introduced into chondrocytes of transgenic (TG) mice, under the control of the cis-regulatory sequences of the human type II collagen gene (COL2A1). Two Escherichia coli β-galactosidase (β-gal)-expressing lines were derived (CIIL73 and CIIL64) as well as two lines (CIINP) expressing influenza A virus nucleoprotein (NP). Expression of the antigens could be demonstrated in cartilaginous tissues. The TG lines showed variable degrees of responsiveness towards the transgene-introduced antigens; whilst 75% of CIIL73 mice had an imparied cytotoxic T lymphocyte (CTL) response towards β-gal, the response in CIIL64 mice was essentially normal. However, both lines displayed normal proliferative and antibody responses to β-gal. A reduced CTL responses was seen to NP in the CIINP lines in ∼65% of the animals. In spite of the persistence of T cells responses to the transgene antigens in these lines, induction of CTL responses alone has so far failed to induce clinical signs of arthritis. Interestingly, some animals expressing β-gal were susceptible to arthritis following challenge with type II collagen alone, whilst their non-TG littermates and TG mice from other lines remained unaffected. As β-gal is expressed by E. coli, a component of the normal gut flora, this suggests a possible role for gut-derived immune responses. We believe these lines could form the basis of a model for studying links between intestinal inflammation and arthritis.link_to_subscribed_fulltex