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S Wadsworth

Publications and source records attributed to S Wadsworth.

30 records · Page 2Linked to original sources
PubMed1990

Origin and selection of peripheral CD4-CD8- T cells bearing alpha/beta T cell antigen receptors in autoimmune gld mice.

We have analyzed the origin and development of unusual CD4-CD8- alpha/beta T cell receptor-positive peripheral T cells produced in large numbers by mice homozygous for the gld mutation (C3H-gld/gld). These mice may be an important model for investigating processes controlling T cell development. Bone marrow transfers demonstrated that the gld defect was intrinsic to bone marrow-derived cells. Clonal deletion of potentially autoreactive cells was observed in peripheral gld CD4-CD8-, CD4+CD8-, and CD4-CD8+ T cells, as well as mature thymocytes. This suggests that gld CD4-CD8- T cells have passed through the thymus in ontogeny and that gld autoimmunity does not result from a general defect in elimination of self-reactive thymocytes. These observations, combined with demethylation of the CD8 gene in the CD4-CD8- population, support prior expression of CD4 and/or CD8 in gld CD4-CD8- T cell ontogeny, perhaps at a CD4+CD8+ stage. Steroid sensitivity of gld thymocytes and CD4-CD8- T cells was normal. Therefore, we found no gross abnormalities in two major mechanisms of inducible cell death in the gld thymus, the clonal deletion process associated with tolerance and the steroid-inducible endogenous endonuclease thought to be involved in apoptosis of unselected thymocytes. The data suggest that if gld CD4-CD8- T cells arise via escape from normal elimination in the thymus, they must do so by a novel defect in thymic selection (perhaps related to aberrant positive signals) and/or are expanded by an extrathymic process which allows clonal deletion to occur.

Animals↗
PubMed1990

Mechanisms of autoimmunity in the context of T-cell tolerance: insights from natural and transgenic animal model systems.

There are a number of mechanisms which cooperate to produce and maintain T-cell tolerance. First, and perhaps most important, is the clonal deletion in the thymus of T cells with high affinity for self antigens. However, to ensure that a wide repertoire of T cells is available in the periphery to combat foreign antigens, the threshold of clonal deletion may be set low enough so that T cells whose TCR's have sub-threshold affinity for self antigens mature and migrate to the periphery. T cells which recognize self antigen-derived peptides not expressed or presented in the thymus will also fail to be deleted. For those self-reactive T cells which are not deleted in the thymus, other mechanisms may produce tolerance, including an undefined alteration of signalling pathways which produces clonal anergy, and lowering the avidity of the TCR for its ligand by downregulating coreceptor and accessory molecules. Active suppression of T-cell responses in another well-described phenomenon whose mechanism is undefined. From our observations with the model systems discussed here, we have observed three distinct mechanisms by which T-cell tolerance can be circumvented, allowing autoimmune phenomena to occur. These mechanisms may have relevance for different types of autoimmune diseases seen in humans. In gld mice, the autoimmune disease seems to be related to a global defect in T-cell differentiation and function, which allows for the expansion of autoimmune B cells. While we showed that clonal deletion of V beta-bearing T cells is appropriate in certain cases, aberrant lymphokine secretion by the abnormal T cells or disruption of immune system regulation are most probably responsible for allowing autoantibody production. While human lupus erythematosis shares much of the pathology of lpr and gld mice, there is no expansion of T cells with a similar phenotype in human lupus. There are environmental factors which must play a role in the development of human lupus, since the incidence of the disease does not follow an absolute genetic pattern. The escape from clonal deletion and subsequent reactivation of autoimmune T cells which we observed in V beta 8.1 TCR-transgenic mice can be a model for human autoimmune diseases such as multiple sclerosis and type I diabetes, in which T cells are directed against a specific autoantigen. According to this model, susceptibility loci for autoimmune disease such as the MHC would function by producing different repertoires of T cells which in some cases could gain autoreactivity following activation.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1989

Immune response to a molecularly defined internal image idiotope.

A monoclonal anti-idiotope termed 87.92.6 mimics the neutralization/cell-attachment site of the reovirus type 3 hemagglutinin (HA3). The second complementarity determining regions of the VH and VL of 87.92.6 share sequence similarity with a determinant on the HA3. We have used synthetic peptides (termed VH, VL, and Reo peptides, respectively) to probe the immunologic significance of this sequence similarity. Antibodies specific for Reo peptide or VL peptide neutralized reovirus type 3 infectivity. Although Reo peptide was an effective immunogen by itself, free VL peptide or VH peptide were unable to elicit antibodies unless they were linked to each other (VH-VL peptide). Immunization with reo peptide, 87.92.6, or the HA3 elicited a specific lymphocyte proliferative response to VH peptide, indicating that VH peptide may bear an important TH determinant. As found previously for 87.92.6, VL peptide elicited a delayed-type hypersensitivity response specific for reovirus type 3. Reovirus type 3 specific cytolytic lymphocytes specifically lysed targets coated with VH-VL peptide, but not VH or VL peptide alone. These results suggest that immune cross-reactivity between an external Ag and an internal image antibody can be understood at the primary structural level. These observations may have important implications for understanding the development of autoantibodies, network interactions, and the regulation of immune responses.

Amino Acid Sequence↗
PubMed1989

Major histocompatibility complex class I-specific cytolytic T cells, derived from gld mice, lacking Thy-1, CD4, and CD8.

Thy-1 is a major cell surface molecule expressed on murine thymocytes and peripheral T cells. Its physiological function is unknown, but in vitro studies suggest that Thy-1 may transmit activation signals to T cells and may play a role in the growth and/or differentiation of thymocytes [Kroczek, R. A., Gunter, K. C., Seligmann, B. & Shevach, E. M. (1986) J. Immunol. 136, 4379-4384; Kroczek, R. A., Gunter, K. C., Germain, R. N. & Shevach, E. M. (1986) Nature (London) 322, 181-184]. However, not all mouse thymocytes are Thy-1+ [Scollay, R., Wilson, A., D'Amico, A., Kelly, K., Egerton, M., Pearse, M., Wu, L. & Shortman, K. (1988) Immunol. Rev. 104, 81-120]. In addition, C3H-gld/gld mice accumulate large numbers of Thy-1- (and Thy-1+) T-cell antigen receptor-positive CD8- CD4- (double negative) T cells in peripheral lymphoid organs. Our previous studies of these Thy-1- and Thy-1+ double negatives suggested that lack of Thy-1 expression correlated with diminished capacity to respond to T-cell stimuli. In this report, we describe a Thy-1- alpha/beta T-cell receptor-positive major histocompatibility complex-specific cytotoxic T-cell clone derived from C3H-gld/gld lymph node-residing cells. The data show that, at least in this system, Thy-1 (and CD8/CD4) expression is not required for growth, cytolytic activity, or expression of functional T-cell receptor complexes in vitro and raise the possibility that Thy-1 expression may not be obligatory in vivo for development of cytotoxic T-lymphocyte precursors in gld mice.

Animals↗
PubMed1988

The antigen-major histocompatibility complex-T cell receptor interaction. A structural analysis.

In summary, we wish to propose that regions on MHC molecules interact with complementary regions on processed peptide antigens, and that the resultant Ag-MHC complex forms a conformation with separate functional regions that are able to interact with similarly complementary areas on T cell receptors. It is the product of these interactions that determines whether a given peptide Ag is capable of binding the MHC molecule, and whether a given Ag-MHC complex is capable of stimulating a particular T cell. As more becomes known about the molecular aspects of MHC-restricted, Ag-specific T cell activation, it will become clear which amino acid residues on the Ag, MHC, and TCR are involved in these interactions.

Animals↗
PubMed1987

Characterization of Lyt-2-, L3T4- class I-specific cytolytic clones in C3H-gld/gld mice. Implications for functions of accessory molecules and programmed development.

We report the first demonstration of Thy-1+, Lyt-2-, L3T4- MHC-specific CTL clones derived from the Lyt-2-, L3T4- subset of lymph node cells of C3H-gld/gld mice. These clones express alpha/beta heterodimeric TCRs on the cell surface and specifically recognize class I molecules on target cells. Lyt-2 and L3T4 molecules are therefore not essential for the induction, recognition, and killing of antigen-specific CTL. In addition, these studies suggest that antigen specificity development for class I structures may occur before Lyt-2 gene activation in the differentiation of T cells.

Animals↗
PubMed1976

Anatomy of herpes simplex virus DNA. V. Terminally repetitive sequences.

Native DNA from four strains of herpes simplex virus 1 (HSV-1) circularized after digestion with the lambda exonuclease, indicating that the molecules were terminally repetitious. In two strains, the terminal repetition was evident in nearly 50% of the DNA molecules. Maximal circularization was observed when only 0.25 to 0.5% of the DNA was depolymerized by the exonuclease, suggesting that the minimal size of the terminally repetitious regions is in the range of 400 to 800 bases pairs. More extensive exonuclease treatment resulted in a reduction in the frequency of circularization. To determine whether the terminally repetitive regions themselves contained self-annealing sequences that were precluding circularization of more extensively digested DNA, the terminal fragments from HinIII restriction endonuclease digests were isolated, denatured, and tested for their ability to self-anneal. The results of hydroxyapatite column chromatography and electron microscope examination of the terminal regions are consistent with this hypothesis.

Base Sequence↗
PubMed1975

Anatomy of herpes simplex virus DNA. II. Size, composition, and arrangement of inverted terminal repetitions.

Electron microscope studies on self-annealed intact single strands and on partially denatured molecules show that herpes simplex virus 1 DNA consists of two unequal regions, each bounded by inverted redundant sequences. Thus the region L (70 percent of the contour length of the DNA) separates the left terminal region a1b from its inverted repeat b'a'1, each of which comprises 6 percent of the DNA. The region S (9.4 percent of DNA) separates the right terminal region cas (4.3 percent of the DNA) from its inverted repeat a'sc'. The regions of the two termini which are inverted and repeated itnernally differ in topology. Thus, cas is guanine plus cytosine rich, whereas only the terminal 1 percent of the a1b region, designated as subregion a1, is guanine plus cytosine rich.

Base Sequence↗