Rachel Ettinger

Bio: Rachel Ettinger is an academic researcher from Boston University. The author has contributed to research in topics: T cell & Cytotoxic T cell. The author has an hindex of 8, co-authored 9 publications receiving 2209 citations.

Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation

Abstract: Receptor crosslinking of T-cell hybridomas induces cell activation followed by apoptosis. This activation-induced cell death requires de novo synthesis of RNA and proteins, but the actual gene products that provide the death signal have not been identified. We show here that receptor crosslinking induces Fas ligand and upregulates Fas, and that the ensuing engagement of Fas by Fas ligand activates the cell-death programme. Cell death, but not activation, can be selectively prevented by a soluble Fas-immunoglobulin fusion protein. Thus, Fas and Fas ligand are the death-gene products, and their interaction accounts for the molecular mechanism of activation-induced T-cell death.

Participation of target Fas protein in apoptosis pathway induced by CD4+ Th1 and CD8+ cytotoxic T cells

Abstract: The results presented here provide evidence that the presence of Fas protein in target cells is essential to permit cytotoxicity (resulting in apoptosis) mediated by cloned CD4+ Th1 cells. Using mitogen-activated B cells as targets, antigen-dependent lysis by CD4+ Th1 effectors was observed with MRL/MpJ+ but not with MRL/MpJ-lpr targets. The congenic MRL/MpJ-lpr strain is defective in Fas expression. Target cells from various lymphoid tissues of C3H.MRL-lpr mice were also resistant to the lectin-dependent cytotoxicity of Th1 effectors, whereas C3H/HeJ targets were sensitive. Moreover, a rapid DNA fragmentation prior to 51Cr release was induced only in C3H/HeJ targets. Thus, cytotoxicity induced by Th1 effectors correlates with target Fas expression. In contrast to Th1 effectors, CD8+ cytotoxic T lymphocytes (CTLs) killed C3H.MRL-lpr targets. When cytotoxicity was assayed in the presence of EGTA and MgCl2, which chelates extracellular Ca2+ [(Ca2+)ext], only C3H.MRL-lpr targets became resistant to CD8+ CTLs. This (Ca2+)ext-independent cytotoxicity of both Th1 and CD8+ effectors could be inhibited with unlabeled C3H/HeJ thymocytes or with a transfectoma carrying a murine Fas-human mu gene construct. In comparison, C3H.MRL-lpr thymocytes and the nontransfected parental cell line were poor inhibitors. Our study demonstrates that CD4+ Th1 cells and CD8+ CTLs differ in their (Ca2+)ext-dependent cytotoxicity but share a (Ca2+)ext-independent cytotoxicity that requires participation of Fas molecules for cytotoxic signal transduction leading to target apoptosis.

Mature CD4+ T lymphocytes from MRL/lpr mice are resistant to receptor-mediated tolerance and apoptosis.

Abstract: The goal of this study was to examine the functional responses and tolerance susceptibility of T lymphocytes from mice of the autoimmune strain, MRL/lpr. A population of autoreactive CD4+ T cells can be readily expanded from the lymphoid tissues of young lpr mice. Lines of IL-2-producing autoreactive and alloreactive lpr and alloreactive +/+ T cells were developed to study their responses to tolerance-inducing stimuli. Culture of +/+ T cells with high concentrations of immobilized anti-CD3 antibody induces both functional anergy and apoptosis. By contrast, lpr-derived T cell lines are relatively resistant to anergy and apoptosis. The implications of these findings for the development of autoimmunity, and the possible role of the Fas Ag in determining resistance or susceptibility to tolerance, are discussed.

Fas ligand-mediated cytotoxicity is directly responsible for apoptosis of normal CD4+ T cells responding to a bacterial superantigen.

Abstract: Exposure of naive CD4+ T lymphocytes to superantigens such as staphylococcal enterotoxin B (SEB) induces a strong proliferative response. Prolonged exposure or subsequent restimulation of the responding T cell population with SEB leads to the apoptotic events of activation-induced cell death (AICD). However, T cells derived from either Fas-deficient lpr or Fas ligand-deficient gld autoimmune mouse strains, fail to undergo AICD under these conditions. Instead, these autoimmune T cells mount a vigorous proliferative response, suggesting a critical role for Fas/FasL interactions in this form of autoapoptosis. In the current study, we found that SEB-induced AICD was tied to the rapid induction of FasL expression in cells constitutively expressing high levels of Fas. Furthermore, the addition of soluble Fas-IgG fusion protein to the SEB-restimulated cultures blocked AICD and resulted in a 2 degrees proliferative response that was comparable in magnitude and kinetics to that of the lpr and gld T cells. The rapid onset of apoptosis in normal T cells subsequent to restimulation with SEB was in direct contrast to the proliferative response of the initial cultures, even though comparable levels of Fas and FasL RNA were found in T cells after 1 degree and 2 degrees challenge. The clonal expansion of the normal T cells responding to the initial SEB stimulation was, however, dramatically compromised when the normal cells were cocultured with an MRL-lpr responder population; addition of soluble Fas-IgG rescued the normal component of the response. Together, these data demonstrate first, that Fas/FasL interactions are intimately tied to superantigen-induced AICD, a form of autocrine cell death, and second, that FasL-mediated cytotoxicity is responsible for the disappearance of normal CD4+ T cells in lpr cocultures.

A CD40L-targeting protein reduces autoantibodies and improves disease activity in patients with autoimmunity.

Abstract: The CD40/CD40L axis plays a central role in the generation of humoral immune responses and is an attractive target for treating autoimmune diseases in the clinic. Here, we report the generation and clinical results of a CD40L binding protein, VIB4920, which lacks an Fc domain, therefore avoiding platelet-related safety issues observed with earlier monoclonal antibody therapeutics that targeted CD40L. VIB4920 blocked downstream CD40 signaling events, resulting in inhibition of human B cell activation and plasma cell differentiation, and did not induce platelet aggregation in preclinical studies. In a phase 1 study in healthy volunteers, VIB4920 suppressed antigen-specific IgG in a dose-dependent fashion after priming and boosting with the T-dependent antigen, KLH. Furthermore, VIB4920 significantly reduced circulating Ki67+ dividing B cells, class-switched memory B cells, and a plasma cell gene signature after immunization. In a phase 1b proof-of-concept study in patients with rheumatoid arthritis, VIB4920 significantly decreased disease activity, achieving low disease activity or clinical remission in more than 50% of patients in the two higher-dose groups. Dose-dependent decreases in rheumatoid factor autoantibodies and Vectra DA biomarker score provide additional evidence that VIB4920 effectively blocked the CD40/CD40L pathway. VIB4920 demonstrated a good overall safety profile in both clinical studies. Together, these data demonstrate the potential of VIB4920 to significantly affect autoimmune disease and humoral immune activation and to support further evaluation of this molecule in inflammatory conditions.

The Fas Death Factor

Abstract: Fas ligand (FasL), a cell surface molecule belonging to the tumor necrosis factor family, binds to its receptor Fas, thus inducing apoptosis of Fas-bearing cells. Various cells express Fas, whereas FasL is expressed predominantly in activated T cells. In the immune system, Fas and FasL are involved in down-regulation of immune reactions as well as in T cell-mediated cytotoxicity. Malfunction of the Fas system causes lymphoproliferative disorders and accelerates autoimmune diseases, whereas its exacerbation may cause tissue destruction.

The Nuclear Factor NF-κB Pathway in Inflammation

Abstract: The nuclear factor NF-κB pathway has long been considered a prototypical proinflammatory signaling pathway, largely based on the role of NF-κB in the expression of proinflammatory genes including cytokines, chemokines, and adhesion molecules In this article, we describe how genetic evidence in mice has revealed complex roles for the NF-κB in inflammation that suggest both pro- and anti-inflammatory roles for this pathway NF-κB has long been considered the “holy grail” as a target for new anti-inflammatory drugs; however, these recent studies suggest this pathway may prove a difficult target in the treatment of chronic disease In this article, we discuss the role of NF-κB in inflammation in light of these recent studies