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Biomedical subjects

Edith M Janssen

Publications and source records attributed to Edith M Janssen.

8 recordsLinked to original sources
PubMed2006

The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9.

Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.

Animals↗
PubMed2005

Protein kinase C-theta is an early survival factor required for differentiation of effector CD8+ T cells.

CD8(+) T cells are crucial for host defense against invading pathogens and malignancies. However, relatively little is known about intracellular signaling events that control the genetic program of their activation and differentiation. Using CD8(+) T cells from TCR-transgenic mice crossed to protein kinase C-theta (PKCtheta)-deficient mice, we report that PKCtheta is not required for Ag-induced CD8(+) T cell proliferation, but is important for T cell survival and differentiation into functional, cytokine-producing CTLs. Ag-stimulated PKCtheta(-/-) T cells underwent accelerated apoptosis associated with deregulated expression of Bcl-2 family proteins and displayed reduced activation of ERKs and JNKs. Some defects in the function of PKCtheta(-/-) T cells (poor survival and reduced Bcl-2 and Bcl-x(L) expression, CTL activity, and IFN-gamma expression) were partially or fully restored by coculture with wild-type T cells or by addition of exogenous IL-2, whereas others (increased Bim(EL) expression and TNF-alpha production) were not. These findings indicate that PKCtheta, although not essential for initial Ag-induced proliferation, nevertheless plays an important role in promoting and extending T cell survival, thereby enabling the complete genetic program of effector CD8(+) differentiation. The requirement for PKCtheta in different types of T cell-dependent responses may, therefore, depend on the overall strength of signaling by the TCR and costimulatory receptors and may reflect, in addition to its previously established role in activation, an important, hitherto unappreciated, role in T cell survival.

Animals↗
PubMed2005

Anti-T-cell Ig and mucin domain-containing protein 1 antibody decreases TH2 airway inflammation in a mouse model of asthma.

BACKGROUND: The T-cell Ig and mucin domain-containing (TIM) gene locus has been linked to differences in T(H)2 responsiveness and asthma susceptibility in mice. The homologous locus in human subjects harbors the gene for TIM-1, which encodes a receptor for hepatitis A virus and has been linked with decreased susceptibility to atopic disease in hepatitis A virus-seropositive individuals. OBJECTIVE: We investigated the effects of administering antibodies against TIM-1 in a mouse model of allergic asthma to determine whether the treatment could downregulate T(H)2 cytokines and reduce pulmonary inflammation. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to induce airway inflammation. Before the ovalbumin challenge, mice were treated with anti-TIM-1 mAb or a control antibody. RESULTS: Administration of anti-TIM-1 antibody to mice after ovalbumin sensitization and before ovalbumin challenge results in a significant decrease in inflammatory cells in bronchoalveolar lavage fluid compared with administration of a control antibody. The decrease is accompanied by significantly lower antigen-specific production of the T(H)2 cytokines IL-10 and IL-13 by cells from the draining lymph nodes. The T(H)1 cytokine IFN-gamma appears to be unaffected. Analysis of the lungs shows that goblet cell hyperplasia and mucus production and the expression of IL-10 are markedly decreased in anti-TIM-1-treated mice. CONCLUSION: The results indicate that anti-TIM-1 might offer a novel approach to treating asthma.

Animals↗
PubMed2005

CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death.

The 'help' provided by CD4+ T lymphocytes during the priming of CD8+ T lymphocytes confers a key feature of immune memory: the capacity for autonomous secondary expansion following re-encounter with antigen. Once primed in the presence of CD4+ T cells, 'helped' CD8+ T cells acquire the ability to undergo a second round of clonal expansion upon restimulation in the absence of T-cell help. 'Helpless' CD8+ T cells that are primed in the absence of CD4+ T cells, in contrast, can mediate effector functions such as cytotoxicity and cytokine secretion upon restimulation, but do not undergo a second round of clonal expansion. These disparate responses have features of being 'programmed', that is, guided by signals that are transmitted to naive CD8+ T cells during priming, which encode specific fates for their clonal progeny. Here we explore the instructional programme that governs the secondary response of CD8+ T cells and find that helpless cells undergo death by activation-induced cell death upon secondary stimulation. This death is mediated by tumour-necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL). Regulation of Trail expression can therefore account for the role of CD4+ T cells in the generation of CD8+ T cell memory and represents a novel mechanism for controlling adaptive immune responses.

Animals↗
PubMed2003

Upregulation of costimulatory molecules induced by lipopolysaccharide and double-stranded RNA occurs by Trif-dependent and Trif-independent pathways.

Both lipopolysaccharide (LPS) and double-stranded RNA (dsRNA) are adjuvants for the adaptive immune response, inducing upregulation of costimulatory molecules (UCM) on antigen-presenting cells. Trif, an adapter protein that transduces signals from Toll-like receptor 4 (TLR4) and TLR3, permits the induction of many cytokines, including interferon-beta, which signals through the type I interferon receptor. We show here that LPS-induced UCM was strictly dependent on the TLR4-->Trif axis, whereas dsRNA-induced UCM was only partly dependent on the TLR3-->Trif axis. But both LPS- and dsRNA-induced UCM were entirely dependent on type I interferon receptor signaling. These findings show that UCM involves an autocrine or paracrine loop, and indicate that an alternative TLR3-independent, Trif-independent pathway contributes to dsRNA-induced UCM.

Adaptor Proteins, Signal Transducing↗
PubMed2003

CD4+ T cells are required for secondary expansion and memory in CD8+ T lymphocytes.

A long-standing paradox in cellular immunology concerns the conditional requirement for CD4+ T-helper (T(H)) cells in the priming of cytotoxic CD8+ T lymphocyte (CTL) responses in vivo. Whereas CTL responses against certain viruses can be primed in the absence of CD4+ T cells, others, such as those mediated through 'cross-priming' by host antigen-presenting cells, are dependent on T(H) cells. A clearer understanding of the contribution of T(H) cells to CTL development has been hampered by the fact that most T(H)-independent responses have been demonstrated ex vivo as primary cytotoxic effectors, whereas T(H)-dependent responses generally require secondary in vitro re-stimulation for their detection. Here, we have monitored the primary and secondary responses of T(H)-dependent and T(H)-independent CTLs and find in both cases that CD4+ T cells are dispensable for primary expansion of CD8+ T cells and their differentiation into cytotoxic effectors. However, secondary CTL expansion (that is, a secondary response upon re-encounter with antigen) is wholly dependent on the presence of T(H) cells during, but not after, priming. Our results demonstrate that T-cell help is 'programmed' into CD8+ T cells during priming, conferring on these cells a hallmark of immune response memory: the capacity for functional expansion on re-encounter with antigen.

Animals↗
PubMed2002

Immunomodulatory effects of antigen-pulsed macrophages in a murine model of allergic asthma.

Macrophages (Mphi) play an unique role in the activation and regulation of T cells through their ability to modulate specific costimulatory and cytokine signals. Here we investigated the immunomodulatory effects of allergen presentation by Mphi in a murine model of allergic asthma. Purified peritoneal Mphi were pulsed with ovalbumin (OVA) (OVA-Mphi), or the immunodominant epitope OVA(323-339) (OVA(323-339)-Mphi), and characterized for cell surface markers, cytokine production, and antigen-presenting capacity toward OVA(323-339)-specific DO11.10 T cells. Antigen-pulsed Mphi were injected (intravenously) in OVA-sensitized Balb/c mice that were repeatedly challenged with OVA or saline aerosol. Administration of OVA-Mphi inhibited airway eosinophilia and hyperresponsiveness to methacholine concomitant with a reduced interleukin (IL)-4 and IL-5 production by T cells upon OVA stimulation in vitro. Interestingly, OVA-induced IL-10 levels remained unchanged, whereas interferon-gamma could not be detected. In contrast to OVA-Mphi, OVA(323-339)-Mphi administration had no effects on these asthma manifestations. Additional in vitro studies demonstrated that OVA-Mphi, but not OVA(323-339)-Mphi, produced high levels of IL-10 upon interaction with the DO11.10 T cells. This IL-10 production by the OVA-Mphi was dependent on MHC-TCR and CD86-CD28, but not CD80-CD28 or CD40-CD154 interactions. Our data suggest that IL-10 production by allergen presenting Mphi plays a crucial role in successful immunotherapy.

Adjuvants, Immunologic↗