scispace - formally typeset
Search or ask a question
Author

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.


Papers
More filters
Journal ArticleDOI
TL;DR: CD40 mRNA and protein are expressed by neuronal cells, and are increased in differentiated versus undifferentiated N2a and PC12 cells as measured by RT–PCR, western blotting and immunofluorescence staining, which demonstrate a role of CD40 in neuronal development, maintenance and protection in vitro and in vivo.
Abstract: We show here that CD40 mRNA and protein are expressed by neuronal cells, and are increased in differentiated versus undifferentiated N2a and PC12 cells as measured by RT–PCR, western blotting and immunofluorescence staining. Additionally, immunohistochemistry reveals that neurons from adult mouse and human brain also express CD40 in situ. CD40 ligation results in a time-dependent increase in p44/42 MAPK activation in neuronal cells. Furthermore, ligation of CD40 opposes JNK phosphorylation and activity induced by NGF-β removal from differentiated PC12 cells or serum withdrawal from primary cultured neurons. Importantly, CD40 ligation also protects neuronal cells from NGF-β or serum withdrawal-induced injury and affects neuronal differentiation. Finally, adult mice deficient for the CD40 receptor demonstrate neuronal dysfunction as evidenced by decreased neurofilament isoforms, reduced Bcl-xL:Bax ratio, neuronal morphological change, increased DNA fragmentation, and gross brain abnormality. These changes occur with age, and are clearly evident at 16 months. Taken together, these data demonstrate a role of CD40 in neuronal development, maintenance and protection in vitro and in vivo.

120 citations

Journal ArticleDOI
TL;DR: It is concluded that endogenous AICD undergoes tight temporal regulation during the differentiation of neurons and is negatively regulated by JNK3 via phosphorylation of APP at Thr668, which appears to disrupt the stabilizing interaction with Fe65 and thus downregulate A ICD-mediated signaling.
Abstract: β-Amyloid precursor protein (APP) is a conserved and ubiquitous transmembrane glycoprotein strongly implicated in the pathogenesis of Alzheimer's disease but whose normal biological function is unknown. Analogy to the Notch protein suggests that APP is a cell-surface receptor that signals via sequential proteolytic cleavages that release its intracellular domain (AICD) to the nucleus. Because these cleavages are major targets for therapeutic inhibition, it is critical to elucidate their physiological function. AICD is stabilized by Fe65, interacts with the transcriptional factor Tip60, and translocates to the nucleus. Here, we show that endogenous AICD in primary neurons is detectable only during a short period of time during differentiation in culture. During this transient rise, a portion of AICD localizes to the nucleus. Subsequently, phosphorylation of the APP cytoplasmic domain at threonine 668 appears to disrupt the stabilizing interaction with Fe65 and thus downregulate AICD-mediated signaling. Furthermore, we find that the neuron-specific c-Jun N-terminal kinase JNK3, but not JNK1 or JNK2, mediates a substantial portion of this phosphorylation. We conclude that endogenous AICD undergoes tight temporal regulation during the differentiation of neurons and is negatively regulated by JNK3 via phosphorylation of APP at Thr668.

120 citations

Journal ArticleDOI
TL;DR: The data suggest that CO confers potent antiproliferative effects in CD3-activated T lymphocytes and that these antiprology effects in T lymphocyte are mediated by p21Cip1-dependent caspase activity, in particular caspases-8, independent of cGMP and mitogen-activated protein kinase signaling pathways.
Abstract: T lymphocyte activation and proliferation is involved in many pathological processes. We have recently shown that carbon monoxide (CO), an enzymatic product of heme oxyenase-1 (HO-1), confers potent antiproliferative effects in airway and vascular smooth muscle cells. The purpose of this study was to determine whether CO can inhibit T lymphocyte proliferation and then to determine the mechanism by which CO can modulate T lymphocyte proliferation. In the presence of 250 parts per million CO, CD3-activated T lymphocyte proliferation was, remarkably, inhibited by 80% when compared with controls. We observed that the antiproliferative effect of CO in T lymphocytes was independent of the mitogen-activated protein kinase or cGMP signaling pathways, unlike what we demonstrated previously in smooth muscle cells. We demonstrate that CO inhibited caspase-3 and caspase-8 expression and activity, and caspase inhibition with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD-FMK pan-caspase inhibitor) blocked T lymphocyte proliferation. Furthermore, in caspase-8-deficient lymphocytes, the antiproliferative effect of CO was markedly attenuated, further supporting the involvement of caspase-8 in the antiproliferative effects of CO. CO also increased the protein level of p21Cip1, and CO-mediated inhibition of caspase activity is partially regulated by p21Cip1. Taken together, these data suggest that CO confers potent antiproliferative effects in CD3-activated T lymphocytes and that these antiproliferative effects in T lymphocytes are mediated by p21Cip1-dependent caspase activity, in particular caspase-8, independent of cGMP and mitogen-activated protein kinase signaling pathways.

120 citations

Journal ArticleDOI
30 Apr 2001-Oncogene
TL;DR: This work presents a novel probabilistic construct called a “spatially aggregating immune checkpoints” that are able to be distinguished between the immune checkpoints of the immune system and other immune checkpoints.
Abstract: Immunobiology Program, Department of Medicine, University of Vermont, Burlington, Vermont, VT 05405, USA; Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut CT 06520, USA; Howard Hughes Medical Institute and Program in Molecular Medicine, Department of Biochemistry & Molecular Biology, University of Massachussetts Medical School, Worcester, Massachusetts, MA 01605, USA

119 citations

Journal ArticleDOI
TL;DR: These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection and observed TGF-β-activated protein kinase 1-binding protein-1-p38α MAPK association that closely paralleled p38MAPK phosphorylation during Toxoplasma infection of Mφ.
Abstract: The intracellular protozoan Toxoplasma gondii triggers rapid MAPK activation in mouse macrophages (Mphi) We used synthetic inhibitors and dominant-negative Mphi mutants to demonstrate that T gondii triggers IL-12 production in dependence upon p38 MAPK Chemical inhibition of stress-activated protein kinase/JNK showed that this MAPK was also required for parasite-triggered IL-12 production Examination of upstream MAPK kinases (MKK) 3, 4, and 6 that function as p38 MAPK activating kinases revealed that parasite infection activates only MKK3 Nevertheless, in MKK3(-/-) Mphi, p38 MAPK activation was near normal and IL-12 production was unaffected Recently, MKK-independent p38alpha MAPK activation via autophosphorylation was described Autophosphorylation depends upon p38alpha MAPK association with adaptor protein, TGF-beta-activated protein kinase 1-binding protein-1 We observed TGF-beta-activated protein kinase 1-binding protein-1-p38alpha MAPK association that closely paralleled p38 MAPK phosphorylation during Toxoplasma infection of Mphi Furthermore, a synthetic p38 catalytic-site inhibitor blocked tachyzoite-induced p38alpha MAPK phosphorylation These data are the first to demonstrate p38 MAPK autophosphorylation triggered by intracellular infection

119 citations


Cited by
More filters
28 Jul 2005
TL;DR: PfPMP1)与感染红细胞、树突状组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�ly.
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。

18,940 citations

Journal ArticleDOI
TL;DR: A procedure for preparing extracts from nuclei of human tissue culture cells that directs accurate transcription initiation in vitro from class II promoters, including tRNA and Ad 2 VA, is developed.
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).

10,800 citations

Journal ArticleDOI
TL;DR: 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 apoptoses in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptotic proteins.
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.

10,744 citations

Journal ArticleDOI
24 Feb 2006-Cell
TL;DR: New insights into innate immunity are changing the way the way the authors think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.

10,685 citations