Richard A. Flavell

Bio: Richard A. Flavell is an academic researcher from Yale University. The author has contributed to research in topics: Immune system & T cell. The author has an hindex of 231, co-authored 1328 publications receiving 205119 citations. Previous affiliations of Richard A. Flavell include National Institute for Medical Research & University of Michigan.

Pulmonary overexpression of IL-9 induces Th2 cytokine expression, leading to immune pathology

Abstract: IL-9 is a pleiotropic cytokine with multiple functions on many cell types involved in the pathology of human asthma. The constitutive overexpression of IL-9 in the lungs of transgenic mice resulted in an asthma-like phenotype. To define the contribution of IL-9 to lung inflammation we generated transgenic mice in which lung-specific expression of the IL-9 transgene is inducible by doxycycline. Transgene induction resulted in lymphocytic and eosinophilic infiltration of the lung, airway epithelial cell hypertrophy with mucus production, and mast cell hyperplasia, similar to that seen in mice that constitutively expressed IL-9 in their lungs. Various cytokines, including IL-4, IL-5, and IL-13, were expressed in the lung in response to IL-9. Blockade of IL-4 or IL-5 following IL-9 induction reduced airway eosinophilia without affecting mucus production. In contrast, neutralization of IL-13 completely abolished both lung inflammation and mucus production. These findings suggest that pathologic changes in the lung require additional signals beyond IL-9, provided by IL-4, IL-5, and IL-13, to develop fully.

Defective Antigen Processing in GILT-Free Mice

Abstract: Processing of proteins for major histocompatibility complex (MHC) class II-restricted presentation to CD4-positive T lymphocytes occurs after they are internalized by antigen-presenting cells (APCs). Antigenic proteins frequently contain disulfide bonds, and their reduction in the endocytic pathway facilitates processing. In humans, a gamma interferon-inducible lysosomal thiol reductase (GILT) is constitutively present in late endocytic compartments of APCs. Here, we identified the mouse homolog of GILT and generated a GILT knockout mouse. GILT facilitated the processing and presentation to antigen-specific T cells of protein antigens containing disulfide bonds. The response to hen egg lysozyme, a model antigen with a compact structure containing four disulfide bonds, was examined in detail.

Beta-globin gene inactivation by DNA translocation in gamma beta-thalassaemia.

Abstract: The beta-globin gene present on the deletion locus in a Dutch gamma beta-thalassaemic patient was found to be identical to the normal beta-globin gene with respect to DNA sequence and its transcription in HeLa cells. DNase I sensitivity and methylation experiments show that the affected beta-globin gene is present in an inactive configuration in vivo. This is the result of a translocation of a normally inactive locus next to the beta-globin gene on the affected chromosome, or the deletion of sequences which are normally required for the maintenance of the active state.

Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice.

Abstract: The expression of the ligand for CD40 (CD40L) is critical for induction of T cell-dependent Ab responses. To examine how critical the expression of CD40L is for induction of cell-mediated immune responses, the ability of T cells from CD40L knockout mice to activate macrophage effector function was assessed. CD4+ T cells from CD40L-knockout mice were fourfold less effective than +/+ T cells in activating the nitric oxide response in allogeneic macrophages. CD40L-knockout T cells that were fixed with paraformaldehyde after a 6-h activation period, a time point at which CD40L dominates the macrophage-activating capability of the T cell, could activate neither macrophage production of inflammatory cytokines (TNF-alpha) nor generation of reactive nitrogen intermediates. After 24 h of activation, however, both CD40L-knockout and +/+ T cells could induce similar but weak responses from the macrophages. This study demonstrates that animals deficient in CD40L expression display a deficiency in T cell-dependent macrophage-mediated immune responses.

T-cell tolerance by clonal anergy in transgenic mice with nonlymphoid expression of MHC class II I-E.

Abstract: T-CELL reactivity to the class II major histocompatibility complex I-E antigen is associated with T-cell antigen receptors containing the Vβ gene segments Vβ17a (ref. 1) and Vβ5 (ref. 2). Mice expressing I-E with the normal tissue distribution (on B cells, macrophages, dendritic cells and thymic epithelium) induce tolerance to self I-E by clonal deletion in the thymus3. By contrast, we find that transgenic INS-I-E mice that express I-E on pancreatic β-cells, but not in the thymus or peripheral lymphoid organs, are tolerant to I-E (ref. 4) but have not deleted Vβ5- and Vβ17a-bearing T cells. Moreover, whereas T-cell populations from nontransgenic mice proliferate in response to receptor crosslinking with Vβ5- and Vβ17a-specific antibodies, T cells from INS-I-E mice do not. Thus, our experiments provide direct evidence that T-cell tolerance by clonal paralysis5–9 does occur during normal T-cell development in vivo.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei

Abstract: We have developed a procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters. Conditions of extraction and assay have been optimized for maximum activity using the major late promoter of adenovirus 2. The extract also directs accurate transcription initiation from other adenovirus promoters and cellular promoters. The extract also directs accurate transcription initiation from class III promoters (tRNA and Ad 2 VA).

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.