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Jonathan Sprent

Publications and source records attributed to Jonathan Sprent.

14 recordsLinked to original sources
PubMed2003

Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules.

T cell stimulation usually requires direct contact with viable antigen-presenting cells (APCs). However, we show here that small exosome-like membrane vesicles shed from APCs can be recognized by naïve CD8+ T cells in the absence of viable APCs. T cell antigen receptor-dependent binding of vesicles by CD8+ cells is MHC class I/peptide-specific and requires that the vesicles coexpress intercellular adhesion molecule 1 (ICAM-1, CD54), although not B7 (B7-1). In the absence of B7, T cell binding of vesicles is nonimmunogenic. By contrast, vesicles expressing both ICAM-1 and B7 are strongly immunogenic and cause purified APC-depleted CD8+ cells to mount peptide-specific proliferative responses and differentiate into effector cells.

Animals↗
PubMed2003

Cytokines and T cell homeostasis.

In recent years it has become apparent that the long-term survival of T cells requires continuous contact with external stimuli. At least two types of stimuli, namely self antigens and cytokines, are involved in maintaining T cell viability. As discussed here, the factors controlling T cell survival and turnover in vivo differ considerably from one T cell subset to another.

Animals↗
PubMed2003

Turnover of memory-phenotype CD8+ T cells.

Memory-phenotype (CD44(hi)) T cells are presumed to represent the long-lived progeny of T cells responding to various environmental antigens. For CD8+ T cells, the background rate of proliferation (turnover) of memory-phenotype cells is increased following exposure to infectious agents. This increase in turnover is controlled by interferons (IFN-I and IFN-gamma) and is mediated by IL-15. Unlike IFNs, IL-15 is directly stimulatory for CD44(hi) CD8+ cells. In addition to controlling proliferation of these cells, IL-15 may also play a vital role in keeping CD44(hi) CD8+ cells alive.

Animals↗
PubMed2002

Interleukin 15 controls both proliferation and survival of a subset of memory-phenotype CD8(+) T cells.

Previous work has shown that memory-phenotype CD44(hi) CD8(+) cells are controlled by a cytokine, interleukin (IL)-15. However, the dependency of CD44(hi) CD8(+) cells on IL-15 is partial rather than complete. Here, evidence is presented that CD44(hi) CD8(+) cells comprise a mixed population of IL-15-dependent and IL-15-independent cells. The major subset of CD122(hi) CD44(hi) CD8(+) cells is heavily dependent on IL-15 by three different parameters, namely (1) "bystander" proliferation induced via IFN-induced stimulation of the innate immune system, (2) normal "background" proliferation, and (3) T cell survival; IL-15 dependency is most extreme for the Ly49(+) subset of CD122(hi) CD44(hi) CD8(+) cells. In contrast to CD122(hi) cells, the CD122(lo) subset of CD44(hi) CD8(+) cells is IL-15 independent; likewise, being CD122(lo), CD44(hi) CD4(+) cells are IL-15 independent. Thus, subsets of memory-phenotype T cells differ radically in their sensitivity to IL-15.

Adoptive Transfer↗
PubMed2002

Interleukin (IL)-15 and IL-7 jointly regulate homeostatic proliferation of memory phenotype CD8+ cells but are not required for memory phenotype CD4+ cells.

The overall size and composition of the pool of naive and memory T cells are tightly regulated by homeostatic mechanisms. Recent work has shown that homeostasis of naive T cells is controlled by two factors, self-major histocompatibility complex (MHC)/peptide ligands and a cytokine, interleukin (IL)-7. In particular, contact with these two factors is required for naive CD4+ and CD8+ cells to undergo "homeostatic" proliferation, i.e., proliferation induced as a consequence of severe T cell depletion. In contrast to naive T cells, the factors that drive memory T cells to undergo homeostatic proliferation are poorly understood. To address this issue, purified memory phenotype CD4+ and CD8+ cells from normal mice were adoptively transferred into various gene-knockout mice rendered T cell-deficient by sublethal irradiation. Three findings are reported. First, unlike naive T cells, homeostatic proliferation of memory T cells is largely MHC independent. Second, memory CD8+ cells can utilize either IL-7 or IL-15 to undergo homeostatic proliferation; however, in the absence of both IL-7 and IL-15, homeostatic proliferation fails to occur. Third, unlike memory CD8+ cells, homeostatic proliferation of memory CD4+ cells is independent of IL-7 and IL-15 (also IL-4). Thus, the homeostatic proliferation mechanisms that control memory CD8+ cells and memory CD4+ cells are quite distinct.

Animals↗
PubMed2002

Overexpression of interleukin (IL)-7 leads to IL-15-independent generation of memory phenotype CD8+ T cells.

Transgenic (TG) mice expressing a high copy number of interleukin (IL)-7 cDNA under the control of the major histocomaptability complex (MHC) class II promoter display a 10-20-fold increase in total T cell numbers. Here, we show that the increase in T cell numbers in IL-7 TG mice is most apparent at the level of memory phenotype CD44hi CD122hi CD8+ cells. Based on studies with T cell receptor (TCR) TG mice crossed to IL-7 TG mice, increased levels of IL-7 may provide costimulation for TCR recognition of self-MHC ligands and thus cause naive CD8+ cells to proliferate and differentiate into memory phenotype cells. In addition, a marked increase in CD44hi CD122hi CD8+ cells was found in IL-7 TG IL-15(-) mice. Since these cell are rare in normal IL-15(-) mice, the dependency of memory phenotype CD8+ cells on IL-15 can be overcome by overexpression of IL-7.

Animals↗
PubMed2002

T memory cells: quality not quantity.

Immunological memory to pathogens is associated with clonal expansion and heightened responsiveness of antigen-specific T cells. Recent work emphasizes that, for efficient protective immunity, qualitative changes in T memory cells are vitally important.

Animals↗
PubMed2002

Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells.

Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44(hi) CD8(+) cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44(hi) CD8(+) cells reflected an inhibitory influence of the aged host environment. Aged CD44(hi) CD8(+) cells also showed poor in vivo responses to IL-15 and IL-15-inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44(hi) CD8(+) cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44(hi) CD8(+) cells. Hence, the reduced turnover of aged CD44(hi) CD8(+) cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44(hi) CD8(+) cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti-IFN-I antibody. Hence the selective reduction in the turnover of aged CD44(hi) CD8(+) cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels.

Adoptive Transfer↗
PubMed2002

Regulation of naïve and memory T-cell homeostasis.

Recent work has confirmed the existence of homeostatic mechanisms that regulate the overall size and composition of the mature T-cell pool. Homeostatic mechanisms not only control total T-cell numbers but appear to act differently on naïve vs. memory cells. The roles of self-MHC/peptide ligands and certain cytokines in T-cell homeostasis are discussed.

Animals↗
PubMed2002

The thymus and negative selection.

Maintenance of tolerance to self antigens is presumed to reflect a combination of central and peripheral tolerance. For T cells, central tolerance occurs during early T cell development in the thymus and causes cells with strong reactivity to self antigens to be destroyed in situ (negative selection). Here, we summarize evidence that negative selection can occur in the thymic medulla and affects a population of semimature HSA+ T cells. The influence of costimulatory molecules, Fas and cytokines on negative selection is discussed.

Animals↗
PubMed2001

T cell memory.

Typical immune responses lead to prominent clonal expansion of antigen-specific T and B cells followed by differentiation into effector cells. Most effector cells die at the end of the immune response but some of these cells survive and form long-lived memory cells. The factors controlling the formation and survival of memory T cells are reviewed.

Adjuvants, Immunologic↗