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.

Regulated expression of an introduced MHC H-2K bm1 gene in murine embryonal carcinoma cells.

Abstract: The transplantation antigens H-2K, H-2D and H-2L are developmentally regulated, highly polymorphic cell surface proteins encoded by the major histocompatibility gene complex (MHC). First detectable on the early embryo, they are subsequently expressed on most somatic cells of the adult mouse in association with the protein beta2-microglobulin (beta 2 M; ref. 5). Cultured F embryonal carcinoma (EC) cells can be induced to differentiate along alternative pathways to form either parietal or visceral9 extra-embryonic endoderm, each concomitant with a change in morphology and pattern of gene expression. Previous reports have demonstrated an increased level of transplantation antigens in differentiated F9 EC cells, but the cell types expressing them were not defined. Here we show that the level of MHC H-2Kb and beta 2 M transcripts is increased during both pathways of this differentiation. Expression of a foreign MHC H-2Kbm1 gene was found to be regulated in a similar manner when the gene was introduced into EC cells. In contrast, an introduced rabbit beta-globin gene was not regulated but expressed constitutively.

Topological organization of multi-chromosomal regions by Firre

Abstract: RNA is known to be an abundant and important structural component of the nuclear matrix, including long noncoding RNAs (lncRNA). Yet the molecular identities, functional roles, and localization dynamics of lncRNAs that influence nuclear architecture remain poorly understood. Here, we describe one lncRNA, Firre, that interacts with the nuclear matrix factor hnRNPU, through a 156 bp repeating sequence and Firre localizes across a ~5 Mb domain on the X-chromosome. We further observed Firre localization across at least five distinct trans-chromosomal loci, which reside in spatial proximity to the Firre genomic locus on the X-chromosome. Both genetic deletion of the Firre locus or knockdown of hnRNPU resulted in loss of co-localization of these trans-chromosomal interacting loci. Thus, our data suggest a model in which lncRNAs such as Firre can interface with and modulate nuclear architecture across chromosomes.

MAP Kinase Phosphatase 5 Protects Against Sepsis-induced Acute Lung Injury

Abstract: Mitogen-activated protein kinases (MAPKs) play a critical role in inflammation. Although activation of MAPK in inflammatory cells has been studied extensively, much less is known about the inactivation of these kinases. MAPK phosphatase 5 (MKP5) is a member of the dual-specificity phosphatase family that dephosphorylates activated MAPKs. Here we report that MKP5 protects sepsis-induced acute lung injury. Mice lacking MKP5 displayed severe lung tissue damage following LPS challenge, characterized with increased neutrophil infiltration and edema compared with wild-type (WT) controls. In response to LPS, MKP5-deficient macrophages produced significantly more inflammatory factors including inflammatory cytokines, nitric oxide, and superoxide. Phosphorylation of p38 MAPK, JNK, and ERK were enhanced in MKP5-deficient macrophages upon LPS stimulation. Adoptive transfer of MKP5-deficient macrophages led to more severe lung inflammation than transfer of WT macrophages, suggesting that MKP5-deficient macrophages directly contribute to acute lung injury. Taken together, these results suggest that MKP5 is crucial to homeostatic regulation of MAPK activation in inflammatory responses.

OspB Antibody Prevents Borrelia burgdorferi Colonization of Ixodes scapularis

Abstract: Borrelia burgdorferi outer surface protein OspB is expressed by spirochetes in the Ixodes scapularis gut. ospB is transcribed from a bicistronic operon with ospA, a known spirochete adhesion gene in the tick gut. Here we examine whether OspB also has a specific function in ticks. OspB specifically binds to a protein or protein complex within the tick gut. We also assessed whether selected nonborreliacidal OspB antibodies or F(ab)2 fragments interfere with B. burgdorferi-tick attachment in vivo. We examined engorged ticks that fed on B. burgdorferi N40-infected scid mice that had been treated with OspB F(ab)2 fragments. Control F(ab)2 fragments did not interfere with B. burgdorferi colonization of the tick gut, whereas OspB F(ab)2 fragments significantly inhibited the attachment of spirochetes to the tick gut. These studies show that nonbactericidal OspB antibodies interfere with B. burgdorferi colonization of I. scapularis, highlighting a specific role for OspB in spirochetearthropod interactions and suggesting new antibody-mediated strategies for interfering with B. burgdorferi transmission.

T-cell TGF-β signaling abrogation restricts medulloblastoma progression.

Abstract: Cancer cell secretion of TGF-β is a potent mechanism for immune evasion. However, little is known about how central nervous system tumors guard against immune eradication. We sought to determine the impact of T-cell TGF-β signaling blockade on progression of medulloblastoma (MB), the most common pediatric brain tumor. Genetic abrogation of T-cell TGF-β signaling mitigated tumor progression in the smoothened A1 (SmoA1) transgenic MB mouse. T regulatory cells were nearly abolished and antitumor immunity was mediated by CD8 cytotoxic T lymphocytes. To define the CD8 T-cell subpopulation responsible, primed CD8 T cells were adoptively transferred into tumor-bearing immunocompromised SmoA1 recipients. This led to generation of CD8(+)/killer cell lectin-like receptor G1 high (KLRG1(hi))/IL-7R(lo) short-lived effector cells that expressed granzyme B at the tumor. These results identify a cellular immune mechanism whereby TGF-β signaling blockade licenses the T-cell repertoire to kill pediatric brain tumor cells.

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.