Michal Tal

All Publications

• A functional subset of CD8+ T cells during chronic exhaustion is defined by SIRPalpha expression. Nature communications Myers, L. M., Tal, M. C., Torrez Dulgeroff, L. B., Carmody, A. B., Messer, R. J., Gulati, G., Yiu, Y. Y., Staron, M. M., Angel, C. L., Sinha, R., Markovic, M., Pham, E. A., Fram, B., Ahmed, A., Newman, A. M., Glenn, J. S., Davis, M. M., Kaech, S. M., Weissman, I. L., Hasenkrug, K. J. 2019; 10 (1): 794

  Abstract

  Prolonged exposure of CD8+ T cells to antigenic stimulation, as in chronic viral infections, leads to a state of diminished function termed exhaustion. We now demonstrate that even during exhaustion there is a subset of functional CD8+ T cells defined by surface expression of SIRPalpha, a protein not previously reported on lymphocytes. On SIRPalpha+ CD8+ T cells, expression of co-inhibitory receptors is counterbalanced by expression of co-stimulatory receptors and it is only SIRPalpha+ cells that actively proliferate, transcribe IFNgamma and show cytolytic activity. Furthermore, target cells that express the ligand for SIRPalpha, CD47, are more susceptible to CD8+ T cell-killing in vivo. SIRPalpha+ CD8+ T cells are evident in mice infected with Friend retrovirus, LCMV Clone 13, and in patients with chronic HCV infections. Furthermore, therapeutic blockade of PD-L1 to reinvigorate CD8+ T cells during chronic infection expands the cytotoxic subset of SIRPalpha+ CD8+ T cells.

  View details for PubMedID 30770827

• Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Tal, M. C., Sasai, M., Lee, H. K., Yordy, B., Shadel, G. S., Iwasaki, A. 2009; 106 (8): 2770-2775

  Abstract

  Autophagy is a highly conserved process that maintains homeostasis by clearing damaged organelles and long-lived proteins. The consequences of deficiency in autophagy manifest in a variety of pathological states including neurodegenerative diseases, inflammatory disorders, and cancer. Here, we studied the role of autophagy in the homeostatic regulation of innate antiviral defense. Single-stranded RNA viruses are recognized by the members of the RIG-I-like receptors (RLRs) in the cytosol. RLRs signal through IPS-1, resulting in the production of the key antiviral cytokines, type I IFNs. Autophagy-defective Atg5(-/-) cells exhibited enhanced RLR signaling, increased IFN secretion, and resistance to infection by vesicular stomatitis virus. In the absence of autophagy, cells accumulated dysfunctional mitochondria, as well as mitochondria-associated IPS-1. Reactive oxygen species (ROS) associated with the dysfunctional mitochondria were largely responsible for the enhanced RLR signaling in Atg5(-/-) cells, as antioxidant treatment blocked the excess RLR signaling. In addition, autophagy-independent increase in mitochondrial ROS by treatment of cells with rotenone was sufficient to amplify RLR signaling in WT cells. These data indicate that autophagy contributes to homeostatic regulation of innate antiviral defense through the clearance of dysfunctional mitochondria, and revealed that ROS associated with mitochondria play a key role in potentiating RLR signaling.

  View details for DOI 10.1073/pnas.0807694106

  View details for Web of Science ID 000263652900055

  View details for PubMedID 19196953

• Mx1 reveals innate pathways to antiviral resistance and lethal influenza disease SCIENCE Pillai, P. S., Molony, R. D., Martinod, K., Dong, H., Pang, I. K., Tal, M. C., Solis, A. G., Bielecki, P., Mohanty, S., Trentalange, M., Homer, R. J., Flavell, R. A., Wagner, D. D., Montgomery, R. R., Shaw, A. C., Staeheli, P., Iwasaki, A. 2016; 352 (6284): 463-466

  Abstract

  Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and Tlr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and Tlr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

  View details for DOI 10.1126/science.aaf3926

  View details for Web of Science ID 000374479700048

  View details for PubMedID 27102485

• Mitochondrial DNA stress primes the antiviral innate immune response NATURE West, A. P., Khoury-Hanold, W., Staron, M., Tal, M. C., Pineda, C. M., Lang, S. M., Bestwick, M., Duguay, B. A., Raimundo, N., MacDuff, D. A., Kaech, S. M., Smiley, J. R., Means, R. E., Iwasaki, A., Shadel, G. S. 2015; 520 (7548): 553-?

  Abstract

  Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)-IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling and type I interferon responses during infection. Our results further demonstrate that mitochondria are central participants in innate immunity, identify mtDNA stress as a cell-intrinsic trigger of antiviral signalling and suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical virus sensing mechanisms to fully engage antiviral innate immunity.

  View details for DOI 10.1038/nature14156

  View details for Web of Science ID 000353334500046

  View details for PubMedID 25642965

• Autophagy and selective deployment of Atg proteins in antiviral defense INTERNATIONAL IMMUNOLOGY Yordy, B., Tal, M. C., Hayashi, K., Arojo, O., Iwasaki, A. 2013; 25 (1): 1-10

  Abstract

  Autophagy is an evolutionarily ancient process eukaryotic cells utilize to remove and recycle intracellular material in order to maintain cellular homeostasis. In metazoans, the autophagy machinery not only functions in this capacity but also has evolved to perform a diverse repertoire of intracellular transport and regulatory functions. In response to virus infections, the autophagy machinery degrades viruses, shuttles viral pathogen-associated molecular patterns to endosomes containing Toll-like receptors, facilitates viral-antigen processing for major histocompatibility complex presentation and transports antiviral proteins to viral replication sites. This is accomplished through canonical autophagy or through processes involving distinct subsets of the autophagy-related genes (Atgs). Herein, we discuss how the variable components of the autophagy machinery contribute to antiviral defense and highlight three emerging themes: first, autophagy delivers viral cytosolic components to several distinct endolysosomal compartments; second, Atg proteins act alone, as subgroups or collectively; and third, the specificity of autophagy and the autophagy machinery is achieved by recognition of triggers and selective targeting by adaptors.

  View details for DOI 10.1093/intimm/dxs101

  View details for Web of Science ID 000313127400001

  View details for PubMedID 23042773

• Mitoxosome: a mitochondrial platform for cross-talk between cellular stress and antiviral signaling IMMUNOLOGICAL REVIEWS Tal, M. C., Iwasaki, A. 2011; 243: 215-234

  Abstract

  Evidence is accumulating that the mitochondria form an integral platform from which innate signaling takes place. Recent studies revealed that the mitochondria are shaping the innate response to intracellular pathogens, and mitochondrial function is modulating and being modulated by innate immune signaling. Further, cell biologic analyses have uncovered the dynamic relocalization of key components involved in cytosolic viral recognition and signaling to the mitochondria, as well as the mobilization of mitochondria to the sites of viral replication. In this review, we provide an integrated view of how cellular stress and signals following cytosolic viral recognition are intimately linked and coordinated at the mitochondria. We incorporate recent findings into our current understanding of the role of mitochondrial function in antiviral immunity and suggest the existence of a 'mitoxosome', a mitochondrial oxidative signalosome where multiple pathways of viral recognition and cellular stress converge on the surface of the mitochondria to facilitate a coordinated antiviral response.

  View details for DOI 10.1111/j.1600-065X.2011.01038.x

  View details for Web of Science ID 000295016800017

  View details for PubMedID 21884179

• Autophagic control of RLR signaling AUTOPHAGY Tal, M. C., Iwasaki, A. 2009; 5 (5): 749-750

  Abstract

  Innate immunity to viral infection is initiated within the infected cells through the recognition of unique viral signatures by pattern recognition receptors (PRRs) that mediate the induction of potent antiviral factor, type I interferons (IFNs). Infection with RNA viruses is recognized by the members of the retinoic acid inducible gene I (RIG-I)-like receptor (RLR) family in the cytosol. Our recent study demonstrates that IFN production in response to RNA viral ligands is increased in the absence of autophagy. The process of autophagy functions as an internal cleanup crew within the cell, shuttling damaged cellular organelles and long-lived proteins to the lysosomes for degradation. Our data show that the absence of autophagy leads to the amplification of RLR signaling in two ways. First, in the absence of autophagy, mitochondria accumulate within the cell leading to the buildup of mitochondrial associated protein, IPS-1, a key signaling protein for RLRs. Second, damaged mitochondria that are not degraded in the absence of autophagy provide a source of reactive oxygen species (ROS), which amplify RLR signaling in Atg5 knockout cells. Our study provides the first link between ROS and cytosolic signaling mediated by the RLRs, and suggests the importance of autophagy in the regulation of signaling emanating from mitochondria.

  View details for DOI 10.1073/pnas.0807694106

  View details for Web of Science ID 000268205300030

  View details for PubMedID 19571662

• Autophagy and Innate Recognition Systems AUTOPHAGY IN INFECTION AND IMMUNITY Tal, M. C., Iwasaki, A. 2009; 335: 107-121

  Abstract

  Autophagy is an ancient, highly conserved pathway responsible for the lysosomal degradation of cytosolic constituents and organelles that is critical in maintaining cellular homeostasis. Recent studies have illustrated an important interplay between autophagy and the innate immune system. Signaling through innate pattern recognition receptors leads to the induction of autophagy. Autophagy is utilized by the innate immune cells to survey for virus infection through delivery of cytosolic viral replication complexes to the endosomal viral sensors. In another case, key molecules in the autophagy pathway were found to negatively regulate cytosolic sensors of RNA viruses. Moreover, it has recently become apparent that the autophagic machinery is utilized by phagocytic cells for efficient phagocytosis and clearance of extracellular pathogens. These studies shed light on the possibility that molecules classically thought to be dedicated to the process of autophagy may function in important physiological processes independent of autophagy, whereby the double-membrane structures form within the cytosol to enclose organelles and long-lived proteins. In this chapter, we will highlight key findings relevant to the role of the autophagic machinery in the innate immune system.

  View details for DOI 10.1007/978-3-642-00302-8_5

  View details for Web of Science ID 000273774900005

  View details for PubMedID 19802562