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C A Janeway

Publications and source records attributed to C A Janeway.

At least 109 records · Page 6Linked to original sources
PubMed1994

Stimulator cell type influences the response of T cells to staphylococcal enterotoxins.

Responses to the superantigen Mls are characterized by proliferation of a significant percentage of T cells expressing receptors encoded by one or a few V beta gene segments. Apparently similar responses are elicited by the staphylococcal enterotoxins (SEs) and other bacterial superantigens. We have observed that T cells can be stimulated by the bacterial superantigen SEs presented by either spleen cells or fibroblasts transfected with the appropriate MHC class II genes. However, the results in this study showed that T cells required more than 100-fold higher concentrations of SEA in the presence of L cell transfectants than spleen APC, although T cell responses to SEB and several other toxins presented by the two types of APC were equivalent. Thus, L cell transfectants have a selective defect in presenting SEA. These data suggest that fibroblasts lack a component required by SEA to stimulate certain T cells, and lead us to propose an alternative model for bacterial superantigen mitogenesis in which the superantigen binds to and modifies the behavior of an endogenous co-ligand.

Animals↗
PubMed1994

Signals and signs for lymphocyte responses.

The adaptive immune response protects us from infection in a world of pathogens that is forever evolving new variants. As the system is built on the generation of an open repertoire of receptors, the recognition of self is unavoidable, and is guarded against by deletion during lymphocyte development of those cells that are specific for ubiquitous self antigens, and the silencing of those that are specific for self antigens only encountered after cells achieve functional maturity in the periphery. This silencing occurs when lymphocytes recognize antigens in the absence of suitable costimulatory molecules. By contrast, when the same cell encounters the same ligand on a cell that expresses costimulatory molecules, it will proliferate and differentiate into an effector cell. These effector cells mediate protective immunity when the antigen is carried by a pathogen, but they can mount autoimmune responses if the antigen is derived from self. The major costimulatory molecules for CD4 T cells appear to be B7 and B7.2 that bind to the CD28 and CTLA-4 receptors on the T cell. The signals from the TCR appear to be integrated with those from the costimulator receptor, and the T cell response depends on the precise nature of these signals, further conditioned by cytokines present in the environment of the responding cell. B cells can be viewed in a similar way, with the costimulatory molecule CD40 ligand and cytokines coming mainly from CD4 helper T cells determining the fate of the responding B cell. The TCR is not simply an on and off switch, since the precise way in which the TCR is ligated determines the differentiation of the T cell and can alter the effector responses of established T cell lines. Thus, the response capabilities of T cells are more flexible than originally believed, and much of this flexibility comes from the interplay of TCR signals and signs from the environment. If the biochemical nature of these differential signaling pathways were known, it might be possible to develop simple pharmacological agents capable of diverting T cell responses from harmful to innocuous by getting the T cell to reinterpret the signals it is receiving via its receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Induction of B cell costimulatory function by recombinant murine CD40 ligand.

T cell-dependent regulation of B cell growth and differentiation involves an interaction between CD40, a B cell surface molecule, and the CD40 ligand (CD40L) which is expressed on activated CD4+ T cells. In the current study, we show that recombinant membrane-bound murine CD40L induces B cells to express costimulatory function for the proliferation of CD4+ T cells. CD40L- or lipopolysaccharide (LPS)-activated, but not control-cultured B cells were strong costimulators of anti-CD3 or alloantigen-dependent T cell responses. The molecular interactions responsible for the increased costimulatory functions were examined by analyzing the activated B cells for changes in the expression of two costimulatory molecules, B7 and heat-stable antigen (HSA), as well as by the use of antagonists of B7 and HSA (CTLA4.Fc and 20C9, respectively). The expression of both B7 and HSA was enhanced on B cells activated with LPS. As observed in previous studies, the costimulatory activity of the LPS-activated B cells was dependent on both B7 and HSA and was completely inhibited in the presence of a combination of CTLA4.Fc and 20C9. In contrast, activation of B cells with CD40L induced the expression of B7 but did not enhance the expression of HSA. In addition the costimulatory activity of the CD40L-activated B cells was partially, but not completely, inhibited by the combination of CTLA4.Fc and 20C9. These results demonstrate that CD40L regulates costimulatory function of B cells in part by inducing the expression of B7 and suggest that CD40L-activated B cells express an additional costimulatory activity that is not associated with LPS-activated B cells.

Animals↗
PubMed1994

Both high and low avidity antibodies to the T cell receptor can have agonist or antagonist activity.

Anti-TCR antibodies can activate or block the activation of T cells. In the present experiments, we have shown that different monoclonal antibodies to the same TCR can have either agonist or antagonist activity, and we have examined the relationship between these functional effects and the avidity of the antibody for the TCR. We show here that it is not the avidity of an anti-TCR antibody that determines whether it acts as an agonist or an antagonist. Moreover, we show that monovalent Fab fragments of agonist antibodies produce detectable changes in T cell behavior. These data suggest that T cell activation may involve not just aggregation of the TCR but also some induced change in individual ligated receptors, and that agonists may produce this change while antagonists do not. We argue that similar effects may apply to peptide-MHC ligands as well.

Amino Acid Sequence↗
PubMed1994

The pathogenesis of adoptive murine autoimmune diabetes requires an interaction between alpha 4-integrins and vascular cell adhesion molecule-1.

An adoptive transfer model of insulin-dependent diabetes mellitus (IDDM) in the nonobese diabetic mouse was used to examine the roles of alpha 4-integrin, vascular cell adhesion molecule 1 (VCAM-1); and intercellular adhesion molecule 1 (ICAM-1) in the pathogenesis of autoimmune diabetes. Antibodies specific for both alpha 4-integrin and one of its ligands, VCAM-1, were able to delay onset of diabetes and decrease the incidence of the disease in adoptive transfer studies. This blocking of disease was accompanied by a marked decrease in lymphocytic infiltration of the islets of Langerhans. Furthermore, these antibodies preferentially block entrance of CD4 T cells into the tissue. Antibodies specific for ICAM-1 had little effect on the onset or incidence of IDDM. Thus, we conclude that an alpha 4-integrin-VCAM-1 interaction is important in T cell entry into the islets of Langerhans and in the pathogenesis of IDDM. In addition, the cascade of events leading to T cell transit across endothelium may be different for CD4 and CD8 cells, and may differ depending on the endothelium involved. Our results support the more general conclusion that an alpha 4-integrin-VCAM-1 interaction may be crucial in allowing activated effector CD4T cells to leave the blood and enter tissue to clear infection.

Animals↗
PubMed1993

TAP1-dependent peptide translocation in vitro is ATP dependent and peptide selective.

T cells detect infection of cells by recognizing peptide fragments of foreign proteins bound to class I molecules of the major histocompatibility complex (MHC) on the surface of the infected cell. MHC class I molecules bind peptide in the endoplasmic reticulum, and analysis of mutant cells has demonstrated that an adequate supply of peptides requires the presence of two genes in the MHC class II locus that encode proteins called transporters associated with antigen processing (TAP) 1 and 2. TAP1 and TAP2 are members of the ATP-binding cassette family of membrane translocators. In this study, we demonstrate in a cell-free system that TAP1 is part of an ATP-dependent, sequence-specific, peptide translocator.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

TCR-CD4 and TCR-TCR interactions as distinctive mechanisms for the induction of increased intracellular calcium in T-cell signalling.

Specific activation of CD4 T cells involves recognition of a peptide: MHC class II complex by the heterodimeric alpha beta TCR and its CD4 co-receptor. The activation of T cells initiates a signal transduction cascade that includes a substantial and rapid increase in cytosolic calcium. In this work we study the role of the interactions between the TCR and the CD4 molecule in inducing this [Ca2+]i increase in the cloned CD4 T-cell line D10. Ligating CD3 or the TCR with mAb leads to proliferation of this cloned line and an increase in intracellular free calcium. An exceptional antibody, 16A, was able to stimulate proliferation but did not induce an increase in intracellular free calcium, even when extensively cross-linked with anti-Ig. However, when 16A was cross-linked to CD4 a rise in [Ca2+]i was observed. This demonstrated the ability of TCR-CD4 interactions to trigger a [Ca2+]i response in a situation where no signal was obtained from TCR-TCR interactions. Because CD4 molecules can associate with the TCR, we also studied whether CD4 is involved in the observed increases in intracellular free calcium obtained with other anti-TCR antibodies. This was examined in CD4-negative T cells transfected with cDNA encoding the D10 TCR. These cells could be induced to flux calcium by the same anti-TCR antibodies that gave this response in D10 cells, and again 16A failed to induce such a response. In the transfectants, anti-CD3 antibodies, in contrast to TCR antibodies, could induce a calcium signal in the absence of cross-linking by anti-Ig indicating that CD3 antibodies may signal distinctly from alpha beta TCR ligation. These studies document that antibodies binding different TCR/CD3 epitopes signal distinctively, and that CD4 can participate in, but is not absolutely required for, the induction of increased intracellular calcium.

Animals↗
PubMed1993

Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma.

Cloned CD4 T cell lines that recognize the Ac1-16 peptide of myelin basic protein bound to I-Au were isolated and used to analyze the immunopathogenesis of experimental autoimmune encephalomyelitis (EAE). T helper type 1 (Th1) clones induced disease, while Th2 clones did not. Using variants of a single cloned Th1 line, the surface expression of alpha 4 integrins (very late antigen 4 [VLA-4]) was identified as a major pathogenic factor. Encephalitogenic clones and nonencephalitogenic variants differ by 10-fold in their level of surface expression of alpha 4 integrin and in their ability to bind to endothelial cells and recombinant vascular cell adhesion molecule 1 (VCAM-1). The alpha 4 integrin-high, disease-inducing cloned Th1 T cells enter brain parenchyma in abundance, while alpha 4 integrin-low, nonencephalitogenic Th1 cells do not. Moreover, antibodies to alpha 4 integrin, its ligand VCAM-1, and intercellular adhesion molecule 1 all influence the pathogenicity of this encephalitogenic clone in vivo. The importance of the expression of VLA-4 for encephalitogenicity is not unique to cloned T cell lines, as similar results were obtained using myelin basic protein-primed lymph node T cells. alpha 4 integrin levels did not affect antigen responsiveness or production of the Th1 cytokines interleukin 2, interferon gamma, and lymphotoxin/tumor necrosis factor beta; and antibodies against alpha 4 integrin did not block antigen recognition in vitro. Thus, we conclude that surface expression of alpha 4 integrin is important in CD4 T cell entry into brain parenchyma. A general conclusion of these studies is that alpha 4 integrins may be crucial in allowing activated effector T cells to leave blood and enter the brain and other tissues to clear infections.

Animals↗
PubMed1993

Type 1 diabetes mellitus: an imbalance between effector and regulatory T cells?

Abundant evidence now exists that autoimmunity plays a critical role in the pathogenesis of type 1 (insulin-dependent) diabetes mellitus. The non-obese diabetic (NOD) mouse is an extensively studied animal model of this T-cell-mediated autoimmune disease. Our laboratory has focused on isolating diabetogenic T cell clones from NOD mice as a means of elucidating the pathogenesis of type 1 diabetes. This experimental approach presupposes that type 1 diabetes in NOD mice results from the action of islet-reactive T cells that are not present in other mouse strains; the diabetogenic T cells would therefore represent "forbidden clones" which exist in NOD mice as a result of a failure of clonal deletion. While the inappropriate presence of diabetogenic T cells probably plays a central role in murine diabetes, it cannot explain all aspects of the disease. Type 1 diabetes is a chronic disorder with a lengthy preclinical stage; if the diabetogenic T cells acted in an unopposed fashion, one might expect to see a much more fulminant clinical course. This observation suggests that regulatory influences are likely to exist in this disease--a possibility supported by recent experimental data. If these regulatory influences could be identified and enhanced, specific immunotherapy for type 1 diabetes could be achieved.

Animals↗
PubMed1993

Gamma delta T-cell lines isolated from intestinal epithelium respond to a B-cell lymphoma.

gamma delta T-cell hybrid clones were obtained from intestinal intraepithelial lymphocytes (i-IEL) by fusion with the BW5147 thymoma line. Four clones which expressed different V gamma/V delta genes were selected for further study. All of the gamma delta clones secreted interleukin-2 (IL-2) in the presence of the BALB/c-derived B-lymphoma line, A20. No alpha beta T-cell hybrid clones derived from spleen or i-IEL responded to A20. We obtained several pieces of evidence which strongly suggest that these responses are mediated by the gamma delta T-cell receptor (TcR). Class II major histocompatibility complex (MHC), FcR and surface Ig expressed on A20 are not involved in the response. Native i-IEL derived from BALB/c selectively survive in culture in the presence of A20 cells. The ligand may be a superantigen-like molecule because all our gamma delta T-cell clones responded to A20 in spite of their different combinations of V gamma/V delta gene segments.

Animals↗