Search PubMed⌕ Search

Biomedical subjects

Stephen C Jameson

Publications and source records attributed to Stephen C Jameson.

32 records · Page 2Linked to original sources
PubMed2003

Distinct effects of STAT5 activation on CD4+ and CD8+ T cell homeostasis: development of CD4+CD25+ regulatory T cells versus CD8+ memory T cells.

Using transgenic mice that express a constitutively active version of STAT5b, we demonstrate that STAT5 plays a key role in governing B cell development and T cell homeostasis. STAT5 activation leads to a 10-fold increase in pro-B, but not pro-T, cells. Conversely, STAT5 signaling promotes the expansion of mature alphabeta T cells (6-fold increase) and gammadelta and NK T cells (3- to 4-fold increase), but not of mature B cells. In addition, STAT5 activation has dramatically divergent effects on CD8(+) vs CD4(+) T cells, leading to the selective expansion of CD8(+) memory-like T cells and CD4(+)CD25(+) regulatory T cells. These results establish that activation of STAT5 is the primary mechanism underlying both IL-7/IL-15-dependent homeostatic proliferation of naive and memory CD8(+) T cells and IL-2-dependent development of CD4(+)CD25(+) regulatory T cells.

Animals↗
PubMed2003

Thymocyte sensitivity and supramolecular activation cluster formation are developmentally regulated: a partial role for sialylation.

TCR reactivity is tuned during thymic development. Immature thymocytes respond to low-affinity self-ligands resulting in positive selection. Following differentiation, T cells no longer respond to low-affinity ligands, but respond well to high-affinity (foreign) ligands. We show in this study that this response includes integrin activation, supramolecular activation cluster formation, Ca(2+) flux, and CD69 expression. Because glycosylation patterns are known to change during T cell development, we tested whether alterations in sialylation influence CD8 T cell sensitivity to low affinity TCR ligands. Using neuraminidase treatment or genetic deficiency in the ST3Gal-I sialyltransferase, we show that desialylation of mature CD8 T cells enhances their sensitivity to low-affinity ligands, although these treatments do not completely recapitulate the dynamic range of immature T cells. These studies identify sialylation as one of the factors that regulate CD8 T cell tuning during development.

Animals↗
PubMed2003

In vivo survival and homeostatic proliferation of natural killer cells.

While the specificity and development of natural killer (NK) cells have been intensely studied, little is known about homeostasis of the mature NK population. Here we show that mouse NK cells undergo homeostatic proliferation when transferred into NK-deficient Rag-/- gammaC-/- hosts. Normal NK functional activity is maintained during this process, although there are some changes in NK phenotype. Using cell sorting, we demonstrate that mature (Mac-1hi) NK cells undergo homeostatic proliferation in an NK-deficient environment, yet immature (Mac-1lo) NK cells also proliferate in such hosts. We find that mature NK cells survive but do not proliferate in hosts which possess an endogenous NK pool. However, we go on to show that mature NK survival is critically dependent on interleukin (IL)-15. Surprisingly, NK survival is also compromised after transfer of cells into IL-15Ralpha-/- mice, implying that IL-15 responsiveness by bystander cells is critical for NK maintenance. These data imply that, similar to T cells, homeostasis of the NK pool is much more dynamic than previously appreciated and this may be relevant to manipulation of NK cells for therapeutic purposes.

Adoptive Transfer↗
PubMed2003

Competition for self ligands restrains homeostatic proliferation of naive CD4 T cells.

T cell antigen receptor (TCR) diversity is a critical feature of adaptive immunity. However, restriction of TCR diversity is a potential risk during immune reconstitution by homeostatic proliferation. What peripheral mechanisms are in place to maintain TCR diversity during recovery from lymphopenia? Here, we examine competition between several monoclonal CD4 T cell populations in RAG(-/-) and TCR Tg RAG(-/-) environments. The results suggest that specific self ligands constitute a critical limiting resource essential for homeostatic proliferation of naive CD4 T cells. In addition, T cells ignore large numbers of competitors as long as their TCR specificity is different and other non-MHC resources are not limiting. Therefore, the numbers of self ligands expressed in the periphery set the limits on TCR diversity.

Animals↗
PubMed2003

Differential role for IL-7 in inducing lung Kruppel-like factor (Kruppel-like factor 2) expression by naive versus activated T cells.

Kruppel-like Factor 2 [KLF2, also called lung Kruppel-like factor (LKLF)] is a transcription factor shown to be necessary for the maintenance of naive T cells. KLF2 is expressed in both naive and memory cells, and is proposed to promote quiescence in these populations. During T cell stimulation, both KLF2 protein and mRNA are down-regulated, and loss of KLF2 appears to be critical for full T cell activation. It is unclear, however, how KLF2 expression is maintained in naive T cells. Recently it was proposed that IL-7, which is known to promote KLF2 re-expression in antigen-stimulated T cells, may also induce KLF2 expression in naive T cells. Here we address this issue by comparing the impact of IL-7 on KLF2 expression in naive and activated T cells. Use of bcl-2 transgenic T cells allowed us to uncouple the requirements for IL-7 in preserving naive T cell survival from its role in maintaining KLF2 expression. Our data demonstrates that IL-7 signals are not required for KLF2 maintenance in naive T cells, suggesting that this cytokine has distinct effects on KLF2 expression in naive versus activated T cells.

Animals↗
PubMed2002

Positive and negative selection of T cells.

A functional immune system requires the selection of T lymphocytes expressing receptors that are major histocompatibility complex restricted but tolerant to self-antigens. This selection occurs predominantly in the thymus, where lymphocyte precursors first assemble a surface receptor. In this review we summarize the current state of the field regarding the natural ligands and molecular factors required for positive and negative selection and discuss a model for how these disparate outcomes can be signaled via the same receptor. We also discuss emerging data on the selection of regulatory T cells. Such cells require a high-affinity interaction with self-antigens, yet differentiate into regulatory cells instead of being eliminated.

Animals↗
PubMed2002

A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter.

Using a previously described human keratin 14 (K14) promoter, we created mice expressing a peptide Ag (OVAp) in epithelial cells of the skin, tongue, esophagus, and thymus. Double transgenic mice that also express a TCR specific for this Ag (OT-I) showed evidence for Ag-driven receptor editing in the thymus. Surprisingly, such mice exhibited a severe autoimmune disease. In this work we describe the features of this disease and demonstrate that it is dependent on CD8 T cells. Consistent with the Ag expression pattern dictated by the human K14 promoter, an inflammatory infiltrate was observed in skin and esophagus and around bile ducts of the liver. We also observed a high level of TNF-alpha in the serum. Given that Ag expression in the thymus induced development of T cells with dual TCR reactivity, and that dual-reactive cells have been suggested to have autoimmune potential, we tested whether they were a causal factor in the disease observed here. We found that OT-I/K14-OVAp animals on a recombinase-activating gene-deficient background still suffered from disease. In addition, OT-I animals expressing OVA broadly in all tissues under a different promoter did not experience disease, despite having a similar number of dual-specific T cells. Thus, in this model it would appear that dual-reactive T cells do not underlie autoimmune pathology. Finally, we extended these observations to a second transgenic system involving 2C TCR-transgenic animals expressing the SIY peptide Ag with the hK14 promoter. We discuss the potential relationship between autoimmunity and self-Ags that are expressed in stratified epithelium.

Animals↗
PubMed2002

The three screen doors: can marine "protected" areas be effective?

The great majority of marine protected areas (MPAs) fail to meet their management objectives. So MPAs can be effective conservation tools, we recommend two paradigm shifts, the first related to how they are located and the second related to how they are managed. MPAs are unlikely to be effective if they are located in areas that are subject to numerous, and often uncontrollable, external stressors from atmospheric, terrestrial, and oceanic sources, all of which can degrade the environment and compromise protection. MPA effectiveness is also limited by low institutional and community capacity for management and inappropriate size with respect to ecological needs. In particular, the check list approach to management does not ensure that key threats are dealt with, or that management expenditures provide a quantifiable return. We recommend a business planning approach to MPA management, in which managers focus on the viability of the management system, i.e., the ability of the MPA to provide ecological goods and services to its target users over the long term.

Animals↗
PubMed2002

Rare, structurally homologous self-peptides promote thymocyte positive selection.

Although it is clear that positive selection of T cells involves recognition of specific self-peptide/MHC complexes, the nature of these self-ligands and their relationship to the cognate antigen are controversial. Here we used two complementary strategies to identify naturally occurring self-peptides able to induce positive selection of T cells bearing a specific T cell receptor, OT-I. Both the bioassay- and bioinformatics-based strategies identified the same self-peptides, derived from F-actin capping protein and beta-catenin. These peptides displayed charge conservation at two key TCR contact residues. The biological activity of 43 other self-peptides and of complex peptide libraries directly correlated to the extent of conservation at TCR contact residues. These results demonstrate that selecting self-peptides are rare and can be identified by homology-based search strategies.

Actin Depolymerizing Factors↗
PubMed2002

Sweet 'n' sour: the impact of differential glycosylation on T cell responses.

The fate and functional activity of T lymphocytes depend largely on the precise timing of gene expression and protein production. However, it is clear that post-translational modification of proteins affects their functional properties. Although modifications such as phosphorylation have been intensely studied by immunologists, less attention has been paid to the impact that changes in glycosylation have on protein function. However, there is considerable evidence that glycosylation plays a key role in immune regulation. We will focus here on examples in which differential glycosylation affects the development, survival or reactivity of T cells.

Animals↗