Breaking T cell tolerance to beta cell antigens by merocytic dendritic cells

In type 1 diabetes (T1D), a break in central and peripheral tolerance results in antigen-specific T cells destroying insulin-producing, pancreatic beta cells. Herein, we discuss the critical sub-population of dendritic cells responsible for mediating both the cross-presentation of islet antigen to CD8⁺ T cells and the direct presentation of beta cell antigen to CD4⁺ T cells. These cells, termed merocytic dendritic cells (mcDC), are more numerous in non-obese diabetic (NOD), and antigen-loaded mcDC rescue CD8⁺ T cells from peripheral anergy and deletion, and stimulate islet-reactive CD4⁺ T cells. When purified from the pancreatic lymph nodes of overtly diabetic NOD mice, mcDC can break peripheral T cell tolerance to beta cell antigens in vivo and induce rapid onset T cell-mediated T1D in young NOD mouse. Thus, the mcDC subset appears to represent the long-sought critical antigen-presenting cell responsible for breaking peripheral tolerance to beta cell antigen in vivo.     

Peptide antigens for gamma/delta T cells

γδ T cells express adaptive antigen receptors encoded by rearranging genes. Their diversity is highest in the small region of TCR V–J junctions, especially in the δ chain, which should enable the γδ TCRs to distinguish differences in small epitopes. Indeed, recognition of small molecules, and of an epitope on a larger protein has been reported. Responses to small non-peptides known as phospho-antigens are multi-clonal yet limited to a single γδ T cell subset in humans and non-human primates. Responses to small peptides are multi-clonal or oligo-clonal, include more than one subset of γδ T cells, and occur in rodents and primates. However, less effort has been devoted to investigate the peptide responses. To settle the questions of whether peptides can be ligands for the γδ TCRs, and whether responses to small peptides might occur normally, peptide binding will have to be demonstrated, and natural peptide ligands identified.     

Molecular mechanisms of CRISPR-mediated microbial immunity

Bacteriophages (phages) infect bacteria in order to replicate and burst out of the host, killing the cell, when reproduction is completed. Thus, from a bacterial perspective, phages pose a persistent lethal threat to bacterial populations. Not surprisingly, bacteria evolved multiple defense barriers to interfere with nearly every step of phage life cycles. Phages respond to this selection pressure by counter-evolving their genomes to evade bacterial resistance. The antagonistic interaction between bacteria and rapidly diversifying viruses promotes the evolution and dissemination of bacteriophage-resistance mechanisms in bacteria. Recently, an adaptive microbial immune system, named clustered regularly interspaced short palindromic repeats (CRISPR) and which provides acquired immunity against viruses and plasmids, has been identified. Unlike the restriction–modification anti-phage barrier that subjects to cleavage any foreign DNA lacking a protective methyl-tag in the target site, the CRISPR–Cas systems are invader-specific, adaptive, and heritable. In this review, we focus on the molecular mechanisms of interference/immunity provided by different CRISPR–Cas systems.     

Molecular recognition in applied enzyme chemistry

Molecular recognition impinges upon many fields of biological chemistry, especially those involving catalytic processes. This review gives examples from studies at Strathclyde of both small and macromolecular systems. Mechanism-based enzyme inhibitors are described with reference to dihydrofolate reductase, dihydroorotate dehydrogenase, and cholesterol metabolism. Applications of molecular recognition related to synthetic transformations are discussed in terms of aromatic substitution, chemically modified papain, and catalytic antibodies for Diels-Alder reactions.     

Molecular chaperones in the processing and presentation of antigen to helper T cells

Helper T lymphocytes recognize peptide fragments of antigen bound to Major Histocompatibility Complex (MHC) class II molecules on the surfaces of antigen presenting cells (APC). Antigen processing involves internalization of the antigen into an acidic compartment where the antigen is degraded and the resulting peptide fragments of the antigen are bound to MHC class II molecules and the complexes subsequently displayed at the APC surface. Thus, antigen processing represents a complex, intracellular assembly process which may, like many intracellular protein folding and assembly processes, require the function of molecular chaperones. This contribution focuses on the evidence which suggests that members of the heat shock protein family of molecular chaperones play a role in this pathway.     

Molecular recognition: Models for drug design

The review takes examples, mostly from the recent literature, to illustrate how an understanding of physico-chemical properties and an appreciation of the molecular shape and electronic properties can lead to a better insight into molecular recognition processes. The techniques used to generate 3-dimensional structures of molecules and the influence this information has had on the drug design cycle, are briefly discussed.     

Molecular recognition in applied enzyme chemistry.

Molecular recognition impinges upon many fields of biological chemistry, especially those involving catalytic processes. This review gives examples from studies at Strathclyde of both small and macromolecular systems. Mechanism-based enzyme inhibitors are described with reference to dihydrofolate reductase, dihydroorotate dehydrogenase, and cholesterol metabolism. Applications of molecular recognition related to synthetic transformations are discussed in terms of aromatic substitution, chemically modified papain, and catalytic antibodies for Diels-Alder reactions.     

Molecular recognition in antibodies and its application

The structure and function of immunoglobulins, and the nature of the antibody — antigen interaction are described. Applications of the molecular recognition properties of antibodies are discussed in the areas of immunotherapy, immunoassay, immunotargeting and catalytic antibodies.     

Molecular recognition in antibodies and its application.

The structure and function of immunoglobulins, and the nature of the antibody-antigen interaction are described. Applications of the molecular recognition properties of antibodies are discussed in the areas of immunotherapy, immunoassay, immunotargeting and catalytic antibodies.     

Molecular recognition: models for drug design.

The review takes examples, mostly from the recent literature, to illustrate how an understanding of physico-chemical properties and an appreciation of the molecular shape and electronic properties can lead to a better insight into molecular recognition processes. The techniques used to generate 3-dimensional structures of molecules and the influence this information has had on the drug design cycle, are briefly discussed.     

Biological role of major transplantation antigens in T cell self-recognition

Summary The proposal is made, illustrated and supported by experimental evidence that T cell-mediated immunopathology triggered initially by low- or non-cytopathic infectious agents may cause diseases, susceptibility to which is linked to the major histocompatibility gene complex.This summary is an updated version of the paper given on the occasion of the Paul Ehrlich Prize ceremonies in 1983; it was also presented at the meeting New Trends in Allergy II in München 1985, and is reproduced here with the permission of Springer Verlag, Heidelberg.     

Biological role of major transplantation antigens in T cell self-recognition

The proposal is made, illustrated and supported by experimental evidence that T cell-mediated immunopathology triggered initially by low- or non-cytopathic infectious agents may cause diseases, susceptibility to which is linked to the major histocompatibility gene complex.     

Detection, by direct lymphocyte immunocytotoxicity, of antigens in cells transformed by Rous virus]

The hamster cells transformed by the Rous Sarcoma Virus (V.S.R.) evidenced surface antigenic alterations that were detected by a method of cellular mediated immunocytotoxicity. Immune hamster lymphocytes were added to tritiated proline prelabeled target cells. These lymphocytes were able to lyse specifically the V.S.R. transformed cells.     

Heterophile antigens in Ehrlich ascites tumor cells

Riassunto Gli autori hanno osservato che i sieri di animali immunizzati con cellule del tumore cancro ascite di Ehrlich sono emolitici per gli eritrociti di topo, ratto e montone e presumono che le cellule del tumore di Ehrlich possano contenere frazioni antigene di tipo eterogenetico.     

Detection of human antigens on the surface of mouse cells transformed by chromosome transfer]

Mouse embryo cells, transformed in vitro by the transfer of chromosomes from HeLa human tumour cells, express a surface antigen (s) also found on HeLa cells. This antigen(s), which has been detected both by indirect immunofluoresence and by a 125I-protein A binding assay, is not an antigen(s) shared by both Human and Mouse cells.     

Molecular and cellular mechanisms of T Cell development

The thymus is central to the establishment of a functioning immune system. Here is the place where T cells mature from hematopoietic progenitors, driven by mutual interactions of stromal cells and the developing thymocytes. As a result, different types of T cells are generated, all of which have been carefully selected for the ability to act in host defense towards non-self and against the potential to mount pathogenic self-reactive autoimmune responses. In this review we summarize our present knowlege on the lineage decisions taking place during this development, the selection processes responsible for shaping the T cell antigen-receptor repertoire, the interactions with the stromal components and the signal transduction pathways which transform the interactions with the thymic microenvironment into cellular responses of survival, proliferation, differentiation and, importantly, also of cell death. Received 12 June 2003; received after revision 22 July 2003; accepted 28 July 2003     

Monoclonal antibodies against antigens on breast cancer cells

Summary Of 360 mAb obtained in a cell fusion experiment with the spleen cells of a mouse immunized with a mixture of different human breast carcinoma cells lines, 30 mAb were selected which reacted more strongly with tumor cells than with (noncancerous) fibroblasts. Theses mAb were tested for reactivity with additional types of cancerous and noncancerous tissues. Two mAb showed high tumor selectivity, but the corresponding epitopes on individual tumor cells were heterogeneously expressed. The mAb will be evaluated for in vivo applications.