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S R Webb

Publications and source records attributed to S R Webb.

At least 37 records · Page 2Linked to original sources
PubMed1994

Expansion/deletion of mature T cells exposed to endogenous superantigens in vivo.

Previous studies have shown that in thymectomized hosts exposure of mature T cells to Mlsa (mtv-7) Ag in vivo leads to specific tolerance and the disappearance of Mlsa-reactive V beta 6+ T cells after an initial phase of T cell expansion. To investigate the factors controlling postthymic elimination of mature T cells, we examined T cell responses to Mlsa and other endogenous superantigens in a number of different strain combinations. The results show that the extent of T cell expansion/deletion is influenced by various factors, including the H-2 haplotype of the host and the particular V beta studied. Collectively, the results suggest that the extent of elimination of mature T cells is variable and may be a function of high avidity interactions with APC.

Animals↗
PubMed1994

T-cell activation by superantigens.

Superantigens stimulate powerful T-cell responses that can have marked effects in vivo, sometimes leading to shock or even death. The demonstration that strong T-cell responses to superantigens in vivo can be followed by tolerance, reflecting either clonal elimination or anergy, has provided important insights into how mature T cells can be regulated. Further progress in understanding the factors that control these responses relies heavily on defining the specific interactions between T-cell receptors, superantigens and major histocompatibility complex molecules which lead to T-cell activation as well as on the characterization of the specific signal transduction events and molecules involved in this activation. Significant progress has been made, during the past year, in the first area and these findings are summarized below; though less information is available in the latter area, recent observations relevant to this issue are discussed.

Animals↗
PubMed1993

Exclusion of circulating T cells from the thymus does not apply in the neonatal period.

Although T cells arise in the thymus, migration of mature postthymic T cells back to the thymus is very limited in adult mice and is restricted to activated cells. In neonates, by contrast, we present evidence that circulating CD4+ and CD8+ T cells with a naive/resting phenotype readily enter the thymus after intravenous injection and remain there for prolonged periods. The migration of resting T cells to the neonatal thymus is largely limited to an unusual subset of cells which lacks expression of the lymph node homing receptor, leukocyte-endothelial cell adhesion molecule 1 (LECAM-1) (MEL-14). Migration of mature T cells to the thymus in neonates may be important for self-tolerance induction.

Age Factors↗
PubMed1993

Intrathymic and extrathymic tolerance in bone marrow chimeras.

Parent-->F1 bone marrow (BM) chimeras provide a useful model for studying self tolerance induction. When prepared with supralethal irradiation (1300 cGy) and conditioned with anti-T cell antibodies, parent-->F1 BM chimeras are devoid of host BM-derived cells; host H-2 expression is apparent in both the intrathymic and extrathymic environments but is limited to non BM-derived cells. When parent-->F1 chimeras are injected with T cells from normal parental strain mice, the expression of host H-2 antigens on nonprofessional APC might be expected to induce tolerance through induction of clonal anergy. In practice, this does not occur. Instead, a small proportion of the injected T cells is induced to proliferate and differentiate into effector cells. Tolerance is not seen. Similarly, tolerance is not apparent when thymectomized parent-->F1 chimeras are given parental strain thymus grafts. These findings suggest that the expression of host H-2 antigens in the post-thymic environment of chimeras is not intrinsically tolerogenic for mature T cells or recent thymic emigrants. Interestingly, post-thymic tolerance does occur when parental strain T cells differentiate in the endogenous thymus of chimeras. Thus, when mature CD8+ cells are prepared from thymus vs lymph nodes (LN) of parent-->F1 chimeras, tolerance to host class I antigens is more marked in LN than thymus; this applies to cytotoxic T lymphocyte (CTL) precursors, generated by limiting dilution analysis. It would appear therefore that many of the host-reactive CTL precursors generated in the thymus of chimeras undergo tolerance induction (deletion or irreversible inactivation) in the post-thymic environment. We suggest that such tolerance is a reflection of a covert form of tolerance induced in the thymus: intrathymic contact with host antigens on thymic epithelial cells (TEC) in chimeras does not delete typical CTL precursors, but these cells are rendered "semi-tolerant". When cultured in vitro in the presence of lymphokines, the cells are able to recover and differentiate into CTL. In vivo, however, the cells recognize antigen in the periphery in the relative absence of lymphokines and the cells die. Although host class I expression on TEC in chimeras deletes only a small proportion of CTL precursors, contact with TEC induces strong tolerance of CD8+ cells in terms of helper-independent proliferative responses in vitro and induction of lethal graft-versus-host disease in vivo. We postulate that these latter responses are controlled by high-affinity T cells, whereas typical CTL generated in LDA are predominantly low-affinity cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Factors influencing the fate of T cells responding to Mls antigens.

Although T cell tolerance to self antigens is primarily a reflection of clonal deletion in the thymus, recent evidence suggests that mature T cells are subject to negative regulation in the post-thymic environment: Extrathymic tolerance is the result of clonal anergy in some studies and T cell deletion in others. The factors controlling the induction of anergy versus deletion of mature T cells are still poorly understood. This article summarizes evidence that exposure of T cells to Mls superantigens in vivo leads to a sequence of T cell proliferation, anergy and deletion; anergy appears to reflect persistence of antigen. The biochemical consequences of exposing T cells to superantigens in vitro are discussed.

Animals↗
PubMed1990

Activation of polyphosphoinositide hydrolysis in T cells by H-2 alloantigen but not MLS determinants.

Murine minor lymphocyte-stimulating (Mls) determinants are cell surface antigens that stimulate strong primary T cell responses; the responding T cells display restricted T cell receptor (TCR) V beta gene usage. Interaction of T cells with mitogens or major histocompatibility complex (MHC) antigens activated the polyphosphoinositide (PI) signaling pathway, but this pathway was not triggered by Mls recognition. However, interleukin-2 (IL-2) secretion and proliferation to all three stimuli were comparable. Thus, although recognition of both allo-H-2 and Mls determinants is thought to be mediated by the TCR, these antigens appear to elicit biochemically distinct signal transduction pathways.

Animals↗
PubMed1990

Induction of neonatal tolerance to Mlsa antigens by CD8+ T cells.

Antigen-specific tolerance of T cells to minor lymphocyte stimulatory (Mls) antigens can be induced in mice by neonatal injection of foreign lymphohematopoietic cells. Although immune responses to Mlsa antigens are controlled by B cells, CD8+ T cells were the most effective cell type for induction of Mlsa tolerance. Tolerance was evident in both thymus and lymph nodes and could be induced by as few as 2 x 10(4) CD8+ T cells; these cells were 50 to 100 times as potent as CD4+ cells or B cells in causing functional tolerance and deletion of V beta 6+ T cells. Thus, intrathymic contact with antigens expressed on CD8+ T cells may play an important role in controlling the normal development of tolerance.

Animals↗
PubMed1990

T cell reactivity to MHC molecules: immunity versus tolerance.

The specificity of mature CD8+ and CD4+ T lymphocytes is controlled by major histocompatibility complex (MHC) class I and class II molecules, respectively. The MHC class specificity of T cells is stringent in many assays, but is less evident when cells are supplemented with exogenous lymphokines. The repertoire of T cells is shaped through contact with MHC molecules in the thymus and involves a complex process of positive selection and negative selection (tolerance). Tolerance of immature T cells to MHC molecules can reflect either clonal deletion or anergy and results from intrathymic contact with several cell types, including epithelial cells and cells with antigen-presenting function. Unlike immature T cells, mature T cells are relatively resistant to tolerance induction. In certain situations partial unresponsiveness of mature T cells can be achieved by exposing T cells to foreign MHC molecules expressed on atypical antigen-presenting cells. Tolerance is rarely complete, however, and the precise requirements for tolerizing mature T cells are still unclear.

Animals↗
PubMed1990

Response of mature unprimed CD8+ T cells to Mlsa determinants.

Contrary to existing dogma, evidence is presented that proliferative responses of mature unprimed T cells to Mlsa antigens involve CD8+ cells as well as CD4+ cells. The response of CD8+ cells to Mlsa antigens proved to be heavily dependent on help from CD4+ cells, and responses were stronger in three I-E+ strain combinations than in an I-E- combination. In I-E+ combinations, CD8+ blast cells accounted for 20-25% of the blasts generated from unseparated T cells responding to Mlsa-bearing stimulator cells in vitro; similar findings applied to blast cells generated in vivo. The observation that the majority (greater than or equal to 50%) of Mlsa-stimulated CD8+ cells (and CD4+ cells) were V beta 6+ indicated that CD8+ cells respond to Mlsa antigens, per se, rather than to nonspecific stimuli. Whether CD4+ and CD8+ cells use the same or different H-2-restricting elements to respond to Mlsa antigens has yet to be resolved.

Animals↗
PubMed1990

Tolerogenicity of thymic epithelium.

To attempt to resolve the controversy on the role of thymic epithelial cells (TEC) in tolerance induction, athymic mice were grafted with allogeneic day-14 fetal thymuses treated with deoxyguanosine in vitro. The data indicate that the tolerogenicity of TEC varies considerably according to the antigen and the subpopulation of T cells studied. For cytotoxic CD8+ cells responding to H-2 class I antigens, TEC induce minimal tolerance. For proliferative responses of CD4+ cells, by contrast, TEC induce significant tolerance to H-2 class II antigens but no detectable tolerance to Mlsa antigens.

Animals↗
PubMed1990

Regulation of D-xylose utilization by hexoses in pentose-fermenting yeasts.

The aldopentose D-xylose is one of the most abundant sugars in plant biomass and its efficient microbial utilization is of fundamental importance in the overall bioconversion of lignocellulosic materials into liquid fuels and chemicals. The discovery of pentose-fermenting yeasts in the early 1980's led to world wide interest because of the perceived potential for improved D-xylose fermentation to enhance the prospect of biomass conversions. However, the utilization of D-xylose by pentose-fermenting yeasts can be adversely affected by the hexoses, mainly D-glucose and D-mannose, which are usually present in high amounts in lignocellulosic hydrolysates. Research in the past several years has uncovered some of the regulatory effects of D-glucose on D-xylose utilization. However, much remains unknown about the mechanisms responsible for these effects. This review summarizes the current state of knowledge on the induction, repression and inactivation of D-xylose utilization in pentose-fermenting yeasts.

Journal Article↗
PubMed1989

Restricted tissue distribution of Mlsa determinants. Stimulation of Mlsa-reactive T cells by B cells but not by dendritic cells or macrophages.

Evidence was sought on the tissue distribution of Mlsa determinants, a class of cell-associated non-H-2 alloantigens that is highly immunogenic for unprimed T cells. Whereas normal CD4+ T cells and an Mlsa-reactive T hybridoma gave strong responses to Mlsa-positive stimulator populations containing Ig+ B cells, anti-Mlsa responses to B-depleted stimulators were almost undetectable. The B-depleted stimulators tested included Thy-1- spleen cells from mu-suppressed mice (mice treated with anti-mu antibody from birth) and J11d- preparations of spleen dendritic cells (DC) and peritoneal macrophages (M phi) from normal mice. Each of these populations was strongly immunogenic for allo-H-2-reactive T cells. The failure to detect Mlsa determinants on Ig- APC, i.e., M phi and DC, suggests that Mlsa determinants are not typical H-2-associated peptides. The data are more compatible with a model in which Mlsa determinants represent (or form part of) an integral cell membrane molecule expressed largely, and perhaps exclusively, on B cells. T cells might recognize these molecules only in native form, "processed" Mlsa determinants being nonimmunogenic. Consistent with this possibility, no evidence was found that Mlsa-negative B cells could absorb Mlsa determinants from Mlsa-positive B cells in a chimeric environment.

Animals↗