Showing papers by "Per A. Peterson published in 2001"

The roles of claudin superfamily proteins in paracellular transport.

Abstract: The claudin superfamily consists of at least 18 homologous proteins in humans. These proteins are important structural and functional components of tight junctions in paracellular transport. Complexed with two other integral transmembrane proteins, occludin and junctional adhesion molecule, claudins are located in both epithelial and endothelial cells in all tight junction-bearing tissues. Claudins interact directly with tight junction-specific, membrane-associated guanylate kinase homologues, ZO-1, ZO-2, and ZO-3, and indirectly with AF-6 and the myosin-binding molecule cingulin. These protein-protein interactions promote scaffolding of the tight junction transmembrane proteins and provide a link to the actin cytoskeleton for transducing regulatory signals to and from tight junctions. The distinct permeability properties observed in different epithelia and endothelia seemingly result from the restricted tissue expression, variability of the homopolymer and heteropolymer assembly, regulated transcription and translation, and the subcellular localization of claudin family proteins. Defects in claudins are causatively associated with a variety of human diseases, demonstrating that claudins play important roles in human physiology. In conditions where the cell adhesion function contributed by tight junctions is essential, such as in altered paracellular transport, in proliferative diseases, and during morphogenesis, the claudin superfamily of homologous proteins provides the molecular basis for the uniqueness of tight junctions and emerges as a new target for intervention.

A key role for ICAM-1 in generating effector cells mediating inflammatory responses

Abstract: We investigated how the accessory molecule interactions encountered during T cell priming influence T cell–mediated destruction of insulin-producing β cells and lead to type 1 diabetes. T cell receptor (TCR)-transgenic CD4+ T cells were primed under controlled conditions in vitro before being adoptively transferred into transgenic recipients expressing membrane ovalbumin under the control of the rat insulin promoter (RIP-mOVA). During priming, antigen-presenting cell expression of B7-1 without intracellular adhesion molecule 1 (ICAM-1) led to the generation of effector cells that migrated to the pancreata of RIP-mOVA recipients but did not cause diabetes. In contrast, when T cells were primed with APCs expressing both B7-1 and ICAM-1, pronounced destruction of β cells and a rapid onset of diabetes were observed. Pathogenicity was associated with T cell production of the macrophage-attracting chemokines CCL3 and CCL4. Thus, interactions of lymphocyte function–associated antigen 1 with ICAM-1 during priming induce both qualitative and quantitative alterations in T effector function and induce potentially autodestructive responses.

Costimulation via lymphocyte function-associated antigen 1 in the absence of CD28 ligation promotes anergy of naïve CD4+ T cells

Abstract: The mechanisms controlling induction of anergy at the level of naive CD4+ T cells are poorly understood but thought to reflect limited contact with costimulatory molecules during T cell antigen receptor (TCR) ligation. To clarify this question, naive TCR transgenic CD4+ cells were exposed to specific peptide presented by transfected antigen-presenting cells (APC) expressing MHC class II molecules with defined accessory molecules. Significantly, culturing CD4(+) cells with APC expressing MHC II plus peptide alone elicited early TCR signaling but failed to induce either proliferation or anergy. Culture with APC expressing MHC II plus B7 molecules led to strong proliferation and T cell priming but no anergy. In marked contrast, conspicuous induction of anergy occurred after T cell culture with APC expressing MHC class II and intercellular adhesion molecule-1 (ICAM-1). Thus, at the level of naive CD4(+) cells, anergy induction appears to reflect selective contact with APC expressing ICAM-1 in the absence of B7.

Characterization and regulation of the major histocompatibility complex–encoded proteins Hsp70-Hom and Hsp70-1/2

Abstract: Vertebrate cells contain at least 12 different genes for Hsp70 proteins, 3 of which are encoded in the major histocompatibility complex (MHC) class III region. In the human MHC, these are named Hsp70-1, -2, and -Hom. To characterize these proteins, we have determined their substrate binding specificity, their cellular and tissue distribution, and the regulation of their expression. We show for the first time (1) peptide binding specificity of Hsp70-Hom; (2) endogenous expression of Hsp70-Hom in human cell lines; (3) cytoplasmic location of Hsp70-Hom protein under basal conditions and concentration in the nucleus after heat shock; (4) unique RNA expression profiles in human tissues for each of the MHC-encoded Hsp70s, significantly different from that for the constitutive Hsc70; (5) a relative increase in levels of Hsp70-Hom protein, compared with other Hsp70s, in response to interferon gamma; and (6) a specific increase on lipopolysaccharide (LPS) treatment of in vivo messenger RNA levels for the MHC-encoded Hsp70s and the DnaJ homologue, hdj2, relative to other chaperones. The unique tissue distributions and specific up-regulation by LPS of the MHC-encoded Hsp70s suggest some specialization of functions for these members of the Hsp70 family, possibly in the inflammatory response.

Functional regulation of immunoproteasomes and transporter associated with antigen processing.

Abstract: The central event in the cellular immune response to invading pathogens is the presentation of non-self antigenic peptides by major histocompatibility complex (MHC) class I molecules to cytotoxic T lymphocytes (CTLs). As peptide binding and transport proteins, MHC class I molecules have evolved distinct biochemical and cellular strategies for acquiring antigenic peptides, providing CTLs an extracellular representation of the intracellular antigen content. Whereas efficient generation of MHC class I binding peptides depends on the intracellular, immunoproteasome-mediated proteolysis machinery, translocation of peptides into the lumen of the endoplasmic reticulum requires the endoplasmic reticulum-resident, adenosine 5'-triphosphate (ATP) binding cassette transporter associated with antigen processing (TAP). Here we show, for the first time, that immunoproteasomes, TAP complexes, and MHC class I molecules are physically associated, providing an effective means of transporting MHC class I binding peptides from their sites of generation into the lumen of the endoplasmic reticulum for loading onto MHC class I molecules. In this review, we assess the current understanding of the functional regulation of immunoproteasomes and transporter associated with antigen processing.