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C A Janeway

Publications and source records attributed to C A Janeway.

At least 163 records · Page 9Linked to original sources
PubMed1990

Ligand thresholds at different stages of T cell development.

Certain T cell ligands can stimulate most or all T cells whose receptor is encoded by particular V beta genes. Exposure to these same ligands during intrathymic development leads to deletion of T cells bearing these same receptors. We have utilized one such ligand, staphylococcal enterotoxin B (SEB), to examine the quantitative differences in these two responses. By comparing the dose of SEB required to delete developing T cells in thymic organ culture with that required to stimulate spleen cells to expand clonally, we observe that clonal deletion is one to two orders of magnitude more sensitive to SEB. Because the T cell ligand involves not only SEB but also class II MHC molecules, and because the culture conditions are distinct, this system does not allow one to state that intrathymic T cells are intrinsically more sensitive to negative selection than peripheral T cells are to activation. However, these studies for the first time do establish a quantitative comparison of these two processes and suggest that there is a margin for error built into the clonal deletion process, such that ligands presented in the thymus are 30- to 100-fold more active in clonal deletion than is the same ligand in activation of peripheral T cells. This result agrees well with the observation that naturally occurring unknown ligands associated with I-E can clonally delete cells that are not activated by the same ligand in mixed lymphocyte culture.

Animals↗
PubMed1990

Antibody-activated immunoregulatory T cells are defective in B cell deprived mice.

We have previously shown that antibody bound to hapten-conjugated macrophages influences the contact sensitivity response to the hapten, the effect depending upon the isotype of antibody used. In the present experiments, we have examined the regulation of the contact sensitivity response of mice lacking B cells, in order to determine whether B cells and/or their products play a role in regulating such responses in situ. We have observed that contact sensitivity is normally induced in such B cell depleted mice, in contrast to the previously described failure of such mice to mount proliferative T cell responses to protein antigens. However, virtually all of the immunoregulatory activities previously defined in the contact sensitivity reaction, including those induced by antibody bound to hapten-coupled macrophages, cannot be elicited in these animals. In particular, intravenous injection of either hapten-coupled PEC, or antigen-antibody complexes of the IgG2a isotype on the surface of a hapten-coupled PEC (both of which induce unresponsiveness to contact sensitization in normal mice due to the activation of suppressor T cell activity) actually sensitize B cell deficient mice. Thus, we conclude that B cells or their products play a central role in the development and/or functioning of immunoregulatory cells involved in the control of contact sensitivity responses.

Animals↗
PubMed1989

An explanation for the protective effect of the MHC class II I-E molecule in murine diabetes.

Insulin-dependent diabetes mellitus is widely believed to be an autoimmune disease. Recent onset diabetics show destruction of insulin-secreting pancreatic beta-cells associated with a lymphocytic infiltrate (insulitis), with autoantibodies to beta-cells being found even before the onset of symptoms. Susceptibility to the disease is strongly influenced by major histocompatibility complex (MHC) class II polymorphism in both man and experimental animal models such as the non-obese diabetic (NOD) mouse. As MHC class II molecules are usually associated with dominant immune responsiveness, it was surprising that introduction of a transgenic class II molecule, I-E, protected NOD mice from insulitis and diabetes. This could be explained by a change either in the target tissue or in the T cells presumed to be involved in beta-cell destruction. Recently, several studies have shown that I-E molecules are associated with ontogenetic deletion of T cells bearing antigen/MHC receptors encoded in part by certain T-cell receptor V beta gene segments. To determine the mechanism of the protective effect of I-E, we have produced cloned CD4+ and CD8+ T-cell lines from islets of recently diabetic NOD mice. These cloned lines are islet-specific and pathogenic in both I-E- and I-E+ mice. Both CD4+ and CD8+ cloned T cells bear receptors encoded by a V beta 5 gene segment, known to be deleted during development in I-E expressing mice. Our data provide, therefore, an explanation for the puzzling effect of I-E on susceptibility to diabetes in NOD mice.

Animals↗
PubMed1989

Monoclonal antibodies to murine CD3 epsilon define distinct epitopes, one of which may interact with CD4 during T cell activation.

The TCR is comprised of two variable chains that confer specificity, called alpha:beta or gamma:delta, physically associated with five different molecules that comprise the complex known as CD3. Antibodies to this complex are very useful, as they react with all T lymphocytes. A rat mAb to mouse CD3 has been prepared. It reacts with 100% of T cells in all mouse strains tested but with no other cell type. It binds to the CD3 epsilon chain. This antibody activates cloned T cell lines and normal T cells, provided suitable accessory cells and signals are present. This antibody detects a determinant similar to but not identical with those detected by two previously reported hamster anti-CD3 epsilon antibodies. This antibody fixes C efficiently, and it is thus useful for depletion of T cells from bulk populations. Activation of T cells by one of the three different anti-CD3 epsilon antibodies was inhibited by the Fab fragment of anti-CD4, similar to the effects of anti-CD4 Fab on two previously reported anti-TCR V region antibodies that bind a CD3 epsilon-associated epitope. This further defines a site involving TCR V regions and CD3 epsilon with which CD4 appears to associate during T cell activation.

Animals↗
PubMed1989

IgG anti-DNA autoantibodies within an individual autoimmune mouse are the products of clonal selection.

Although mice from almost all inbred strains produce IgM anti-DNA antibody in response to B cell mitogens, only (NZB x NZW)F1 mice and mice from other strains that are genetically predisposed to autoimmunity spontaneously produce anti-DNA antibody of the IgG isotype. Because (NZB x NZW)F1 mice display marked B cell hyperactivity, anti-DNA antibody production in these mice has been thought to result from spontaneous, polyclonal B cell activation. Although this may be true for IgM anti-DNA antibodies, our results demonstrate that IgG anti-DNA antibodies are not polyclonal. Rather, IgG anti-DNA autoantibodies within an individual autoimmune mouse are oligoclonal and somatically mutated. These results demonstrate that IgG anti-DNA autoantibodies are the products of clonally selective B cell stimulation and exhibit the same characteristics as secondary immune antibodies to conventional immunogens: they are IgG, they are clonally restricted, and they are somatically mutated.

Animals↗
PubMed1989

A novel MHC class II epitope expressed in thymic medulla but not cortex.

The repertoire of receptors expressed by peripheral T cells is the result of two selective events that occur during intrathymic development. Positive selection expands cells able to recognize foreign peptides presented by self MHC molecules, and negative selection eliminates cells reactive to self MHC molecules and associated self peptides. Chimaera studies suggest that, at least in the case of T cells recognizing MHC class II, interaction with thymic cortical epithelial cells is responsible for the former, whereas thymic medullary cells, of bone marrow origin, mediate the latter. This view of thymic development is supported by recent morphometric analyses, showing that autoreactive cells are found in thymic cortex but not medulla. Although numerous studies have shown that MHC class II molecules are expressed in both sites, none provides any explanation for the differential selection of T cells that is observed. Here, we describe a novel MHC class II epitope which is found on cells in thymic medulla but not cortex. The antibody to this epitope reacts with about 10% of class II molecules on B cells and may be recognizing a self peptide-MHC complex. These results provide the first evidence for differential expression of class II epitopes in different tissues and are compatible with the hypothesis that different ligands, rather than different affinity thresholds for the same ligand, are involved in positive and negative selection of the T-cell repertoire.

Animals↗
PubMed1989

Inhibition of the responses of a cloned CD4+ T cell line to different class II major histocompatibility complex ligands by anti-CD4 and by anti-receptor Fab fragments are directly related.

The responses of a single cloned T cell line to three different class II major histocompatibility complex (MHC) ligands have been compared for avidity, determined by inhibition with anti-T cell receptor Fab fragments directed at two different receptor epitopes, and for ease of inhibition with anti-CD4 antibody. It has, thus, been directly demonstrated that ease of inhibition of the response of a T cell to a class II MHC ligand by anti-CD4 is inversely related to the avidity of the T cell receptor for that ligand. The difficulties in inferring from this finding that CD4 acts primarily by increasing receptor avidity for its class II MHC ligand are discussed in the light of evidence suggesting that CD4 is an active signaling component of the T cell receptor for class II MHC ligands.

Animals↗
PubMed1989

Elevated temperature regulates tumor necrosis factor-mediated immune killing.

The effect of elevated temperature (heat/fever) on the regulation of inflammatory processes was studied in an in vitro system. Since tumor necrosis factor (TNF), a central mediator in inflammation, is both a pyrogen and a cytokine capable of inducing the death of certain cells, we examined the relationship between heat shock and TNF-mediated immune killing. Heat shock of WEHI-164 fibrosarcoma cells significantly (and transiently) decreased the sensitivity of these cells to recombinant TNF-mediated lysis and to class II major histocompatibility complex-specific, TNF-secreting inflammatory T cell-mediated lysis. Incubating inflammatory T lymphocytes in elevated temperature transiently abolished their lytic potential and their ability to secrete TNF. Our data show that the pyrogen activity of TNF could control cytolytic processes during inflammation both by inducing protective protein(s) synthesis in target cells and by arresting TNF secretion by effector T lymphocytes.

Animals↗
PubMed1989

Selective induction of growth factor production and growth factor receptor expression by different signals to a single T cell.

Stimulation of lymphokine production and the expression of receptors for growth factors can be dissociated in AK-8, a line of CD4+, I-A-restricted, conalbumin-specific mouse T cells. When activated by antibodies specific for the T cell receptor (TcR; F23.1) or the CD3 complex (145-2C11) adsorbed to plastic culture wells, AK-8 cells produce lymphokines but are unable to proliferate. Proliferation takes place using the same stimuli upon addition of interleukin 1 (IL 1). Autocrine growth induced by anti-TcR, anti-CD3 or by antigen is dependent on IL 4 and not on IL 2 in this cell line, as shown by the effect of antibodies against IL 4 or the IL 2 receptor. Similarly to plastic-adsorbed antibodies, phorbol myristic acetate (PMA) or a combination of PMA and the calcium ionophore Ionomycin also induces secretion of growth factors without inducing proliferation, but in this case addition of IL 1 is ineffective in inducing AK-8 proliferation. When incubated with anti-TcR or anti-CD3 antibodies in soluble form these cells neither proliferate nor produce IL 4 even in the presence of IL 1. However, soluble antibodies in the presence of IL 1 induce enhanced expression of IL 2 receptors, as measured both by induction of responsiveness to exogenous IL 2 or flow cytometry analysis using anti-IL 2 receptor antibodies. These results show that the pathways for the activation of growth factor receptor expression and the induction of lymphokine secretion can be differentiated in this cell line using anti-TcR or anti-CD3 reagents in different physical forms. The transmembrane signals delivered by these different forms of anti-receptor antibody may allow an understanding of these distinct requirements for T cell growth.

Animals↗
PubMed1989

The role of CD4 in T-cell activation: accessory molecule or co-receptor?

CD4 is an MHC class II binding protein found on T cells that recognize peptide fragments of protein antigens bound to MHC class II molecules. In this review, Charlie Janeway argues that CD4 is a physical component of the T-cell receptor, and that CD4 augments signalling via the receptor by about 100-fold. He proposes the term co-receptor to describe this molecule and its functional homologue, CD8.

CD4 Antigens↗
PubMed1989

Diversity in T-cell receptor gamma gene usage in intestinal epithelium.

The intraepithelial cells of the murine small intestine include a significant number of CD3+ T cells that use T-cell receptor gamma genes rather than T-cell receptor beta genes. As with other sites of T-cell receptor gamma expression, combinatorial diversity is limited, but there is junctional diversity, and this, together with the specific variable region gamma gene segments used, distinguishes gamma gene expression in the gut epithelium from that in cells derived from the dermal epithelium. The restriction of productive gamma gene expression largely to one V-J-C (V, variable; J, joining; C, constant) gene combination may result from nonproductive joining of other V-J combinations and from productively rearranged genes rendered nonfunctional by incorrect splicing.

Animals↗
PubMed1989

Recognition of a self major histocompatibility complex TL region product by gamma delta T-cell receptors.

Ligand specificity of a murine gammadelta T-cell receptor-expressing hybridoma (KN6) derived from adult thymocytes has been analyzed in detail. The molecule recognized by the KN6 gammadelta T-cell receptor is expressed on syngeneic cells of various sources (peritoneal macrophages, thymocytes, spleen cells, and Abelson murine leukemia virus-transformed cell lines) and on transformed cells arrested at an early stage of development (e.g., PCC3 embryonal carcinoma cells). Linkage of the gene coding for the KN6 ligand to the major histocompatibility complex genes could be demonstrated by testing KN6 hybridoma reactivity to cells from congenic strains that differ only at H-2. In addition, analysis of recombinant strains indicates that the gene controlling the KN6 ligand is located in or distal to the TL region. Involvement of the KN6 gammadelta T-cell receptor in this recognition process could be directly demonstrated by transferring the KN6 TL specificity after introduction of the productively rearranged KN6 gamma and delta genes into an alphabeta T-cell clone or into the germ line in transgenic mice. These observations raise the possibility that at least some gammadelta cells regulate hemopoietic cell maturation and activation.

Animals↗
PubMed1989

Physical association of CD4 and the T-cell receptor can be induced by anti-T-cell receptor antibodies.

CD4 can physically associate with the CD3-T-cell receptor complex as visualized in cocapping experiments. This association occurs when the T-cell receptor is cross-linked by certain anti-variable region antibodies that appear to induce a conformational change in the receptor such that it associate with CD4. Similar association has been observed in earlier studies with the same cloned helper T cell when the physiological ligand, antigen-class II major histocompatibility complex molecule, is bound by the T-cell receptor. The ability of anti-T-cell receptor antibodies to induce the T-cell receptor-CD4 association correlates with a 100-fold increase in the ability of the antibody to activate the T cell. This suggests that the complex of CD4 and the T-cell receptor act synergistically in T-cell activation, thus readily explaining the commonly observed association of CD4 expression with class II major histocompatibility complex-restricted antigen recognition. This association could also play a role in infection by human immunodeficiency virus.

Animals↗