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Rose Zamoyska

Publications and source records attributed to Rose Zamoyska.

13 recordsLinked to original sources
PubMed2006

Superantigens: supersignalers?

Some bacterial and viral proteins are potent activators of the immune response, earning them the title of superantigens (SAgs). Infection with pathogens containing these proteins can produce massive T cell activation and can result in various potentially fatal conditions, such as toxic shock and food poisoning. Unlike conventional peptide antigens, SAgs bind promiscuously to the external faces of class II major histocompatibility complex (MHC) molecules and families of T cell receptors (TCRs), thereby activating large numbers of T cells simultaneously. The manner in which SAgs bind MHC and TCR differs from the way in which peptide antigens interact with these structures. Nevertheless, because they simultaneously engage MHC and TCR, SAgs were assumed to activate T cells through the canonical signaling pathway that has been described for T cell activation by TCR engagement of peptide-MHC complexes. However, recent research shows that SAgs also activate an alternative signaling pathway in T cells. This study shows that SAgs can stimulate T cells in the absence of the Src family kinase, Lck, by activating a heterotrimeric guanine nucleotide-binding protein (G protein), Galpha(11). Galpha(11) activates phospholipase C-beta (PLC-beta), rather than the more abundant PLC-gamma1, and, by this means, links SAg signaling to the phosphatidylinositol and protein kinase C signaling pathways. The discovery of a signaling pathway specifically activated by SAgs, and not by conventional peptide antigens, opens the possibility of developing therapeutic reagents that may help control diseases caused by these agents.

Antigens, Bacterial↗
PubMed2006

Differential requirement for Lck during primary and memory CD8+ T cell responses.

T cell receptor (TCR) signaling mediates cell fate decisions throughout the life of a T cell. The earliest biochemical events during antigen-stimulated TCR signaling include activation of the Src-family protein tyrosine kinase, p56(Lck) (Lck), which is an integral component of the TCR signaling complex by its association with the cytoplasmic tails of CD8 or CD4. CD8 and Lck are obligatory during thymic selection of CD8+ T cells. What remain unknown are when and with what stringency Lck is required for effective TCR-mediated activation and function throughout the life of a mature CD8+ T cell. Using mice that express an inducible Lck transgene in T cells, we have investigated the temporal importance of Lck-mediated TCR signaling in antigen-specific CD8+ T cell responses during acute viral infections. We show that Lck deficiency induced in naive mice abrogated the antigen-specific activation and clonal expansion of CD8+ T cells during a primary response to acute viral infections. Moreover, the magnitude of primary CD8 T cell expansion depended on the duration of Lck-dependent TCR signaling. Quite unexpectedly, however, Lck was dispensable for enhanced functional avidity, maintenance, and reactivation of memory CD8+ T cells in vitro and in vivo. These observations suggest that the TCR signaling apparatus is rewired from an Lck-dependent state in naive CD8+ T cells to an Lck-independent state in memory CD8+ T cells. Less stringent requirements for antigen-specific TCR signaling to activate memory CD8+ T cells could, in part, account for their unique hyperreactivity to antigen, which contributes to accelerated immune control during secondary infections.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Lck regulates the threshold of activation in primary T cells, while both Lck and Fyn contribute to the magnitude of the extracellular signal-related kinase response.

The src family kinases p56lck (Lck) and p59fyn (Fyn) are the most proximal signaling molecules to be activated downstream of the T-cell receptor. Using an inducible transgenic model, we can regulate the expression of Lck in primary T cells and ask how the signaling cascade and differentiation potential are affected by the absence or the presence of reduced levels of Lck. We show that in naïve T cells, Lck controls the threshold of activation by preferentially regulating multiple signaling pathways that result in the mobilization of Ca2+ through activation of phospholipase C-gamma and protein kinase C as well as activation of the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) pathway. Fyn is also able to stimulate the ERK/MAPK pathway in primary T cells but has little influence on the mobilization of Ca2+. Only Lck efficiently stimulates production of diacylglycerol and therefore RasGRP1 recruitment to the plasma membrane and phosphorylation of Shc, suggesting that Fyn activates ERK via a different upstream signaling route. Finally, we show that signals through Lck are essential for the development of T-cell-effector potential, particularly for effective cytokine transcription.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Do CD8 effector cells need IL-7R expression to become resting memory cells?

The role for IL-7R expression in the differentiation of effector T cells into resting memory remains controversial. Here, using a conditional IL-7R transgenic model, we were able to test directly whether CD8 effector T cells require IL-7R expression for their differentiation into resting memory cells. In the absence of IL-7R expression, effector cells transferred into "full" hosts underwent a protracted and unremitting contraction compared with IL-7R-expressing control cells and were unable to develop into long-term resting memory cells. Surprisingly, when the same effector cells were transferred into empty T-cell-deficient hosts, they could generate long-lived fully functional resting memory cells independently of IL-7R expression. Formation of these latter cells was found to be dependent on IL-15, because the same IL-7R-deficient effector cells were rapidly lost from IL-15-deficient hosts, having a half-life of less than 40 hours. Therefore, our data suggest that, under physiological conditions, both IL-7 and IL-15 synergize to promote the formation of memory cells directly by limiting the contraction of effectors that occurs following an immune response and that reexpression of IL-7R is a key checkpoint in the regulation of this process.

Adoptive Transfer↗
PubMed2004

Signalling in T-lymphocyte development: integration of signalling pathways is the key.

alpha beta T-cell development is restricted to the thymus. Interactions between developing lymphocytes and the thymic stroma, together with bone-marrow-derived monocytes and dendritic cells, are critical for proper development of the T-cell lineage. The developmental sequence through which T-cell progenitors pass on their way to maturity is well established, and can be followed by the sequential acquisition and/or removal of cell surface molecules. Using the combination of modern genetic manipulations, such as transgenesis, gene ablation (knockouts) and targeted mutagenesis (knock-ins), with the ever-improving conditional and inducible manipulation of gene expression, we are beginning to gain an understanding of how intercellular interactions can be relayed via intracellular signalling cascades to bring about nuclear re-organisation and the differentiated mature CD4(+) and CD8(+) subpopulations.

Animals↗
PubMed2003

Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells.

Immunological memory depends on the long-term maintenance of memory T cells. Although the factors that maintain CD8 T cell memory are well understood, those responsible for CD4 memory are not well defined. We have shown here that interleukin 7 (IL-7) was an important survival factor for CD4 memory T cells that together with T cell receptor (TCR) signals regulated homeostasis of the CD4 memory population in lymphopenic conditions and in the intact immune system. Thus, IL-7 contributes to the maintenance of all naive and memory T cell subsets, and therefore controls the overall size of the T cell pool.

Animals↗
PubMed2003

Involvement of avidity for major histocompatibility complex in homeostasis of naive and memory T cells.

The requirements for survival and self-renewal of peripheral T cells and the nature of mechanisms controlling the size of the naive and memory pool are not completely understood. Here, we examine the involvement of the major histocompatibility complex (MHC) in survival and homeostatic expansion of naive and memory T cells. We show that the homeostatic behavior of naive T cell receptor (TCR)-transgenic T cells can be deduced by the expression levels of TCR and CD5, a negative regulator of TCR signaling. Both these factors determine the strength of TCR stimulation by MHC-derived signals. We further show that, similarly to naive T cells, MHC-derived signals influence the homeostatic expansion capacity of memory T cells under lymphopenic conditions. In contrast to naive T cells, however, memory T cells can reach a homeostatic equilibrium, in which survival/self-renewal of each clone is dissociated from their avidity for MHC-derived signals.

Adoptive Transfer↗
PubMed2003

Regulation of peripheral T-cell homeostasis by receptor signalling.

The peripheral T-cell pool is maintained at a constant size throughout life. This is achieved through tight homeostatic regulation of the different T-cell subsets. T cells appear to be able to sense whether the T-cell compartment is full and, if it is not, they are able to respond by undergoing cell division. Recent advances have identified that both signalling through the T-cell receptor and a variety of cytokines are essential for the regulation of these responses.

Animals↗
PubMed2003

The influence of the src-family kinases, Lck and Fyn, on T cell differentiation, survival and activation.

The src-family kinases p56lck (Lck) and p59fyn (Fyn) are expressed in T cells and are among the first signaling molecules to be activated downstream of the T cell receptor (TCR). Evidence is emerging that although closely related, these signaling molecules have discrete functions during development, maintenance and activation of peripheral T cells. For example, during thymopoiesis Lck is uniquely able to provide all the signals required for pre-TCRbeta selection, although Fyn can substitute for a subset of these. Positive selection of CD4 single-positive (SP) cells is also critically dependent on the expression of Lck but not Fyn, while differentiation of CD8 SP cells proceeds relatively efficiently in the absence of Lck. In naïve peripheral T cells either Lck or Fyn can transmit TCR-mediated survival signals, and yet only Lck is able to trigger TCR-mediated expansion signals under conditions of lymphopenia. Stimulation of naïve T cells by antigenic stimuli is also severely compromised in the absence of Lck, but more subtly impaired by the absence of Fyn. We discuss recent experiments addressing how these two src-kinase family members interface with downstream signaling pathways to regulate these diverse aspects of T cell behavior.

Animals↗
PubMed2002

TCR and IL-7 receptor signals can operate independently or synergize to promote lymphopenia-induced expansion of naive T cells.

TCR and cytokine signals induce naive T cells to undergo spontaneous divisions as part of a homeostatic response to conditions of T cell deficiency. The conditions under which these signals evoke the homeostatic response and their interaction with each other are poorly understood, and yet are very important clinically in considering strategies for immune reconstitution. Here, we show that p56(lck) (lck)-mediated TCR signals and IL-7R signals are each able to stimulate T cell proliferation in lymphopenic hosts independently of one another, but can also synergize to facilitate proliferation. Furthermore, the relative contribution to the homeostatic response by TCR and cytokine signals is not fixed and critically depends on both the degree of lymphopenia and specific characteristics of individual T cell clones. Finally, we show that only lck and not fyn can mediate the TCR-driven proliferation, while neither lck nor fyn is required for IL-7R-induced proliferation.

Adjuvants, Immunologic↗
PubMed2002

TCR signals mediated by Src family kinases are essential for the survival of naive T cells.

The role of TCR signals triggered by recognition of self MHCs in maintaining the survival of naive peripheral T cells remains controversial. Here we examine the role of the Src family kinases, p56(lck) (Lck) and p59(fyn) (Fyn), in the survival of naive T cells. We show that long term survival requires a combination of signals transduced by Src family kinases and signals through the IL-7R. In the absence of either one, naive T cells die slowly, but if both signals are removed, cell loss is greatly accelerated. The TCR signal can be mediated by either Fyn or Lck at wild-type levels of expression, but not by Lck alone if expressed suboptimally. The disappearance of T cells in the absence of Fyn and Lck was associated with a complete loss of TCRzeta-chain phosphorylation and down-regulation of CD5, both of which are also MHC contact dependent, indicating that the Src family kinases are critical for transducing a TCR-MHC survival signal.

Animals↗