Showing papers by "David Baltimore published in 2016"

MicroRNAs as regulatory elements in immune system logic

Abstract: MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs.

Domain-swapped T cell receptors improve the safety of TCR gene therapy

Abstract: T cells engineered to express a tumor-specific αβ T cell receptor (TCR) mediate anti-tumor immunity. However, mispairing of the therapeutic αβ chains with endogenous αβ chains reduces therapeutic TCR surface expression and generates self-reactive TCRs. We report a general strategy to prevent TCR mispairing: swapping constant domains between the α and β chains of a therapeutic TCR. When paired, domain-swapped (ds)TCRs assemble with CD3, express on the cell surface, and mediate antigen-specific T cell responses. By contrast, dsTCR chains mispaired with endogenous chains cannot properly assemble with CD3 or signal, preventing autoimmunity. We validate this approach in cell-based assays and in a mouse model of TCR gene transfer-induced graft-versus-host disease. We also validate a related approach whereby replacement of αβ TCR domains with corresponding γδ TCR domains yields a functional TCR that does not mispair. This work enables the design of safer TCR gene therapies for cancer immunotherapy.

Erratum: MicroRNAs as regulatory elements in immune system logic

Abstract: Nature Reviews Immunology 16, 279–294 (2016) In the original version of this article, an incorrect arrowhead was used in Figure 2b, suggesting that factor Y negatively regulates microRNA X. This has now been corrected in the online version of the article to show that factor Y positively regulates microRNA X.

Deficiency of Nuclear Factor-κB c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice.

Abstract: The nuclear factor-κB protein c-Rel plays a critical role in controlling autoimmunity. c-Rel–deficient mice are resistant to streptozotocin-induced diabetes, a drug-induced model of autoimmune diabetes. We generated c-Rel–deficient NOD mice to examine the role of c-Rel in the development of spontaneous autoimmune diabetes. We found that both CD4^+ and CD8^+ T cells from c-Rel–deficient NOD mice showed significantly decreased T-cell receptor–induced IL-2, IFN-γ, and GM-CSF expression. Despite compromised T-cell function, c-Rel deficiency dramatically accelerated insulitis and hyperglycemia in NOD mice along with a substantial reduction in T-regulatory (Treg) cell numbers. Supplementation of isogenic c-Rel–competent Treg cells from prediabetic NOD mice reversed the accelerated diabetes development in c-Rel–deficient NOD mice. The results suggest that c-Rel–dependent Treg cell function is critical in suppressing early-onset autoimmune diabetogenesis in NOD mice. This study provides a novel natural system to study autoimmune diabetes pathogenesis and reveals a previously unknown c-Rel–dependent mechanistic difference between chemically induced and spontaneous diabetogenesis. The study also reveals a unique protective role of c-Rel in autoimmune diabetes, which is distinct from other T-cell–dependent autoimmune diseases such as arthritis and experimental autoimmune encephalomyelitis, where c-Rel promotes autoimmunity.

A path toward understanding neurodegeneration.

Abstract: The specter of neurodegenerative disease, particularly Alzheimer's disease, haunts the developed world and exacts a poorly documented toll on underdeveloped countries. With so little progress made toward finding a cure—or, better, a prevention—it is time to rethink the path to progress. This requires a change in perspective on the type of research that will make a difference. The lesson learned from cancer research is that a new commitment means rethinking the fundamental approach to the disease. Cancer research moved from taking potshots with, usually, cytotoxic drugs to a bottom-up, mechanism-based approach in which newly acquired genetic knowledge played the largest role. Today, that effort has produced a platform of knowledge from which academia and industry are drawing. For neurodegenerative disease, the genetic approach remains valid but the problem must concurrently be approached from a complementary, robust cell biological perspective, focusing on the cellular cascade of events that lead to neuronal cell death.

The boldness of philanthropists

Abstract: Last week, Priscilla Chan and Mark Zuckerberg announced their new philanthropic initiative with the goal of “curing, preventing, and managing all diseases by the end of the century.” This may raise some eyebrows, but this effort—part of the $45 billion Chan Zuckerberg Initiative—joins forces with other philanthropists to push the envelope and support audacious ideas, with long-term commitments, to solve some of our greatest challenges.

Why We Need a Summit on Human Gene Editing

Abstract: In 1981, Matthew Meselson pointed out that the puzzle brought to light by Darwin, of what constitutes heredity, was solved in two tranches. The first lasted from 1900, when Mendel’s work of the last half of the nineteenth century came into the consciousness of the scientific community. It lasted until 1950 or so, when the rules of genetic inheritance had been firmly established.

A poliovirus temperature-sensitive RNA synthesis mutant located in a noncoding region of the genome (poliovirus cDNA/site-directed mutagenesis/persistent viral infection/complementation)

Abstract: We have constructed an 8-base-pair insertion mutation in the 3' noncoding region of an infectious poliovirus cDNA clone that gives rise to a temperature-sensitive RNA synthesis mutant upon transfection into mammalian cells. The mutated cDNA was used to establish a cell line that releases the mutant poliovirus in a temperature-dependent fashion, repre- senting a unique persistent viral infection. A poliovirus mutant mapping in the noncapsid region of the viral genome can be complemented in this cell line, implying that the cell line expresses viral proteins at the nonpermissive temperature. Many events take place in a cell infected by poliovirus. The positive-strand RNA genome of the virus must be replicated, viral proteins made, cellular functions inhibited, and new virions produced. Although much has been learned about these and other aspects of the virus life cycle (1), clear understanding of the functions of the various viral proteins and their interaction with cellular constituents still lies ahead. This is due in part to the lack of well-defined poliovirus mutants. The discovery that a cloned cDNA copy of the poliovirus RNA genome gives rise to infectious poliovirus upon transfection into mammalian cells (2, 3) opened up the possibility of constructing defined poliovirus mutants by mutagenizing the infectious cDNA. The opportunity to store the genetic information encoding a mutant poliovirus as a cDNA clone makes it possible to determine the nucleotide sequence of the mutated genome and to ensure that the mutation is responsible for the observed phenotype. We report here the construction of several linker-insertion mutations in the 3' noncoding region of the viral genome. One of these mutations, PTH7387, gave rise to a temperature- sensitive poliovirus mutant. The infectious cDNA bearing this mutation was used to establish stable persistently infect- ed human HeLa cell lines that release infectious poliovirus at the permissive temperature. Such cell lines, at the non- permissive temperature, can complement another poliovirus mutant, showing that the integrated viral genome is translat- ed.

5'-Terminal structure of poliovirus polyribosomal RNA is pUp (DEAE-paper ionophoresis/mRNA/7-methylguanosine in 5'-5'-pyrophosphate linkage)

Abstract: Poliovirus RNA purified from virus-specific polyribosomes does not contain m7G in a 5'-5'-pyrophosphate linkage at its 5'-end. The only potential 5'-end found in ribonuclease digests of this RNA is pUp, which is present in a yield of 1 mole/mole of poliovirus RNA. We conclude that a 5'-terminal m7G is not required for translation of at least one RNA species in animal cells.

Reduction of caveolin and caveolae in oncogenically

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Legal aids: Science primers in the courtroom.

Abstract: David Neuberger suggests that scientific primers could help to speed up legal proceedings In the United States, the Federal Judicial Center and the National Academies of Sciences, Engineering, and Medicine have prepared such primers for judges in the form of a reference manual (see go.nature.com/ntqkvf).

Human immunodeficiency virus type 1 mRNA expression in peripheral blood cells predicts disease progression independently of the numbers of CD4+ lymphocytes (acquired immunodeficiency syndrome/polymerase chain reaction/3'-azido-3'-deoxythymidine)

Abstract: To address the significance of human immu- nodeficiency virus (HIV) replication in peripheral blood mono- nuclear cells (PBMCs), we have used reverse transcriptase- initiated PCR to measure HIV-1 mRNA expression in PBMC specimens collected from a cohort of HIV-infected individuals during a long-term prospective study. We found dramatic differences in HIV mRNA expression among individuals with very similar clinical and laboratory indices, and this variation strongly correlated with the future course of the disease. No evidence of viral replication was detected in PBMCs from asymptomatic individuals who, thereafter, had normal levels of CD4+ cells for at least 5 years. Irrespective of whether the CD4+ cell numbers were normal at the time of sampling, abundant expression of HIV-1 mRNA in PBMCs predicted accelerated disease progression within the next 2 years. Thus, independently of what may be the rate of HIV replication in other viral reservoirs, such as lymphatic tissue, the amount of HIV mRNA in PBMCs appears to reflect the subsequent development of HIV disease. We have also used the reverse transcriptase-initiated PCR assay to demonstrate a transient response to 3'-azido-3'-deoxythymidine treatment. Determina- tion of HIV-1 mRNA expression in the PBMCs of infected

adhesion molecule-1 up-regulatio

Abstract: Several tumor necrosis factor receptor- associated factor (TRAF) family proteins including TRAF2, TRAF3, TRAF5, and TRAF6, as well as Jak3, have been implicated as potential mediators of CD40 signaling. An extensive in vitro binding study indicated that TRAF2 and TRAF3 bind to the CD40 cytoplasmic tail (CD40ct) with much higher affinity than TRAF5 and TRAF6 and that TRAF2 and TRAF3 bind to different residues of the CD40ct. Using CD40 mutants incapable of binding TRAF2, TRAF3, or Jak3, we found that the TRAF2-binding site of the CD40ct is critical for NF-cB and stress-activated protein kinase activation, as well as the up-regulation of the intercellular adhesion molecule-i (ICAM-1) gene, whereas binding of TRAF3 and Jak3 is dispensable for all of these functions. Overexpression of a dominantly active IKBa strongly inhibited CD40-induced NF-KB activation, ICAM-1 promoter activity, and cell-surface ICAM-1 up-regulation. These studies suggest a potential signal transduction pathway from the CD40 receptor to the transcriptional activation of the ICAM-1 gene.