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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
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Journal ArticleDOI
TL;DR: Comparisons of two Tla-region genes, T3b and its homologue T13c, allow us to conclude that these genes show extraordinarily high sequence conservation, in contrast to alleles of the H- 2K- and H-2D- region genes.
Abstract: The thymus leukemia (TL) antigens, encoded by class I genes in the Tla subregion of the major histocompatibility complex (MHC), are cell surface molecules expressed on thymocytes of certain strains of mice and on certain T-cell leukemias. In order to study the fine structure and interrelationships of genes of the Tla subregion, a Tla-specific probe was isolated from the TL-encoding T13c gene of BALB/c mice (Tlac haplotype). The probe hybridized with two Tla genes in the Tlac haplotype (T13c and T3c) and with only one in the Tlab haplotype (T3b). Examination of this subset of Tla genes (T3b, T3c, and T13c) by restriction enzyme analysis and oligonucleotide hybridization studies confirmed that T3b is the allele of T3c and that T3c and T13c may have arisen by duplication. The T3b gene, while not transcribed in the tissues of the TL- strain C57BL6, was shown to be transcriptionally active in the TL-expressing leukemic cell line ERLD derived from that strain. The T3b gene was cloned and its complete DNA sequence was determined. These data permit complete comparison of two Tla-region genes, T3b and its homologue T13c, and allow us to conclude that these genes show extraordinarily high sequence conservation, in contrast to alleles of the H-2K- and H-2D-region genes. Comparison of T3b with other class I sequences in the H-2 and Qa subregions suggests that the T3-subset genes are the most divergent from other class I genes.

40 citations

Journal ArticleDOI
TL;DR: This approach should allow the recovery of most genes that can be linked to a marker pBR322 sequence and for which a specific phenotype can be selected in a recipient eukaryotic cell.
Abstract: A procedure has been developed to allow the recovery of an integrated plasmid genome from a transformed cell, together with large areas of the flanking DNA sequences. DNA from Saccharomyces cerevisiae BAS2, in which the pBR322--ura 3 plasmid (Y1p5) is integrated at the yeast histone H2A and H2B locus, was used to generate a cosmid library, using a new cosmid vector (pTL5) that is ampicillin sensitive and tetracycline resistant. Colonies were selected for ampicillin resistance, which was conferred by the incorporation of the integrated pBR322 beta-lactamase gene into the recombinant cosmid. Restriction enzyme and blot hybridization analyses show that the rescued clones contain the yeast histone genes in addition to the Y1p5 sequences; a total of approximately 50 kilobase pairs of DNA sequences flanking the plasmid was recovered as a series of overlapping cosmids. This approach should allow the recovery of most genes that can be linked to a marker pBR322 sequence and for which a specific phenotype can be selected in a recipient eukaryotic cell.

40 citations

Journal ArticleDOI
TL;DR: The fact that human CD4 is functional in mice and can be studied in the absence of murine CD4 should facilitate studies of humanCD4 activity in general and human immunodeficiency virus 1 gp120-mediated pathogenesis in acquired immune deficiency syndrome specifically.
Abstract: The ability of a human coreceptor to function in mice was investigated by generating human CD4 (hCD4)-expressing transgenic mice on a mouse CD4-deficient (mCD4-/-) background. From developing thymocyte to matured T lymphocyte functions, hCD4 was shown to be physiologically active. By examining the expansion and deletion of specific V beta T cell families in mutated mice with and without hCD4, it was found that hCD4 can participate in positive and negative selection. Mature hCD4 single positive cells also were found in the periphery and they were shown to restore MHC class II-restricted alloreactive and antigen-specific T cell responses that were deficient in the mCD4 (-/-) mice. In addition, these hCD4 reconstituted mice can generate a secondary immunoglobulin G humoral response matching that of mCD4 wild-type mice. The fact that human CD4 is functional in mice and can be studied in the absence of murine CD4 should facilitate studies of human CD4 activity in general and human immunodeficiency virus 1 gp120-mediated pathogenesis in acquired immune deficiency syndrome specifically.

39 citations

Journal ArticleDOI
TL;DR: The data suggest thatTLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection.
Abstract: TLR3 is known to respond to dsRNA from viruses, apoptotic cells, and/or necrotic cells. Dying cells are a rich source of ligands that can activate TLRs, such as TLR3. TLR3 expressed in the liver is likely to be a mediator of innate activation and inflammation in the liver. The importance of this function of TLR3 during acute hepatitis has not previously been fully explored. We used the mouse model of Con A-induced hepatitis and observed a novel role for TLR3 in hepatocyte damage in the absence of an exogenous viral stimulus. Interestingly, TLR3 expression in liver mononuclear cells and sinus endothelial cells was up-regulated after Con A injection and TLR3−/− mice were protected from Con A-induced hepatitis. Moreover, splenocytes from TLR3−/− mice proliferated less to Con A stimulation in the presence of RNA derived from damaged liver tissue compared with wild-type (WT) mice. To determine the relative contribution of TLR3 expression by hematopoietic cells or nonhematopoietic to liver damage during Con A-induced hepatitis, we generated bone marrow chimeric mice. TLR3−/− mice engrafted with WT hematopoietic cells were protected in a similar manner to WT mice reconstituted with TLR3−/− bone marrow, indicating that TLR3 signaling in both nonhematopoietic and hematopoietic cells plays an important role in mediating liver damage. In summary, our data suggest that TLR3 signaling is necessary for Con A-induced liver damage in vivo and that TLR3 regulates inflammation and the adaptive T cell immune response in the absence of viral infection.

39 citations

Journal ArticleDOI
TL;DR: The laboratory has used reporter transgenic mice, selective hybridization techniques, and studies of cell signaling to show that a complex pattern of gene expression is reprogrammed as the decision is made to become either a Th1 or Th2 cell.
Abstract: Our laboratory has studied the molecular basis of T helper cell differentiation. We have used reporter transgenic mice, selective hybridization techniques, and studies of cell signaling to show that a complex pattern of gene expression is reprogrammed as the decision is made to become either a Th1 or Th2 cell. Many of these components have been identified, and their mechanisms of action elucidated. Understanding these mechanisms is likely to lead in the long-term to ways to intervene in these processes and, therefore, to direct immune response in therapeutically useful directions.

39 citations


Cited by
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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