1: Proc Natl Acad Sci U S A. 2009 Aug 18. [Epub ahead of print]

http://www.ncbi.nlm.nih.gov/pubmed/19706459

T cell receptor sharing by cytotoxic T lymphocytes facilitates efficient virus control.

Chaudhri G, Quah BJ, Wang Y, Tan AH, Zhou J, Karupiah G, Parish CR.

Infection and Immunity Group and Cancer and Vascular Biology Group, Immunology Program, John Curtin School of Medical Research, Australian National University, Canberra ACT 2601, Australia.

A remarkable feature of the adaptive immune system is the speed at which small numbers of antigen-specific lymphocytes can mediate a successful immune response. Rapid expansion of T and B lymphocyte clones that have receptors specific for a particular antigen is one of the primary means by which a swift response is generated. Although much of this clonal expansion is caused by the division of antigen-specific cells, here we demonstrate an additional mechanism by which the pool of effector T cells against a viral infection can quickly enlarge. Our data show that virus-specific CD8(+) cytotoxic T lymphocytes (CTL) can transfer their T cell receptors (TCR) to recipient CTL of an unrelated specificity that, as a consequence, gain the antigen specificity of the donor T cell. This process occurs within minutes via membrane exchange and results in the recipient CTL acquiring the ability to recognize and eliminate cells targeted by the donor TCR, while still retaining the antigen specificity of its own TCR. Such receptor sharing allows rapid, proliferation-independent expansion of virus-specific T cell clones of low frequency and plays a highly significant antiviral role that can protect the host from an otherwise lethal infection.

PMID: 19706459 [PubMed - as supplied by publisher]

3. Immunity, Volume 30, Issue 4, 556-565, 09 April 2009

doi:10.1016/j.immuni.2009.02.005

http://www.cell.com/immunity/abstract/S1074-7613%2809%2900139-3

The NLRP3 Inflammasome Mediates In Vivo Innate Immunity to Influenza A Virus through Recognition of Viral RNA

Irving C. Allen¹,Margaret A. Scull^2,3,Chris B. Moore¹,Eda K. Holl²,Erin McElvania-TeKippe²,Debra J. Taxman²,Elizabeth H. Guthrie¹,Raymond J. Pickles^2,3andJenny P.-Y. Ting^1,2,,

¹ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
² Department of Microbiology and Immunology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
³ Cystic Fibrosis/Pulmonary Research and Treatment Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

Corresponding author

 

Summary

The nucleotide-binding domain and leucine-rich-repeat-containing (NLR) family of pattern-recognition molecules mediate host immunity to various pathogenic stimuli. However, invivo evidence forthe involvement of NLR proteins in viral sensing has not been widely investigated and remains controversial. As a test of the physiologic role of the NLR molecule NLRP3 during RNA viral infection, we explored the invivo role of NLRP3 inflammasome components during influenza virus infection. Mice lacking Nlrp3, Pycard, or caspase-1, but not Nlrc4, exhibiteddramatically increased mortality and a reduced immune response after exposure to the influenza virus. Utilizing analogs of dsRNA (poly(I:C)) and ssRNA (ssRNA40), we demonstrated that an NLRP3-mediated response could be activated by RNA species. Mechanistically, NLRP3 inflammasome activation by the influenza virus was dependent on lysosomal maturation and reactive oxygen species (ROS). Inhibition of ROS induction eliminated IL-1 production in animals during influenza infection. Together, these data place the NLRP3 inflammasome as an essential component in host defense against influenza infection through the sensing of viral RNA.

5: Nature. 2009 May 21;459(7245):433-6. Epub 2009 Apr 1.Links

http://www.ncbi.nlm.nih.gov/pubmed/19339971

Syk kinase signalling couples to the Nlrp3 inflammasome for anti-fungal host defence.

Gross O, Poeck H, Bscheider M, Dostert C, Hannesschläger N, Endres S, Hartmann G, Tardivel A, Schweighoffer E, Tybulewicz V, Mocsai A, Tschopp J, Ruland J.

III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 Munich, Germany.

Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.

PMID: 19339971 [PubMed - indexed for MEDLINE]

6: Nature. 2009 Jan 29;457(7229):557-61. Epub 2009 Jan 11. Links

http://www.ncbi.nlm.nih.gov/pubmed/19136945

Erratum in:

Nature. 2009 Feb 26;457(7233):1168.

Comment in:

Cell Res. 2009 Mar;19(3):277-8.

Nature. 2009 Jan 29;457(7229):544-5.

Adaptive immune features of natural killer cells.

Sun JC, Beilke JN, Lanier LL.

Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, California 94143, USA.

In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.

PMID: 19136945 [PubMed - indexed for MEDLINE]

7: Nature. 2008 Sep 11;455(7210):242-5. Links

http://www.ncbi.nlm.nih.gov/pubmed/18690214

RNA interference screen for human genes associated with West Nile virus infection.

Krishnan MN, Ng A, Sukumaran B, Gilfoy FD, Uchil PD, Sultana H, Brass AL, Adametz R, Tsui M, Qian F, Montgomery RR, Lev S, Mason PW, Koski RA, Elledge SJ, Xavier RJ, Agaisse H, Fikrig E.

Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticutt 06520-8031, USA.

West Nile virus (WNV), and related flaviviruses such as tick-borne encephalitis, Japanese encephalitis, yellow fever and dengue viruses, constitute a significant global human health problem. However, our understanding of the molecular interaction of such flaviviruses with mammalian host cells is limited. WNV encodes only 10 proteins, implying that it may use many cellular proteins for infection. WNV enters the cytoplasm through pH-dependent endocytosis, undergoes cycles of translation and replication, assembles progeny virions in association with endoplasmic reticulum, and exits along the secretory pathway. RNA interference (RNAi) presents a powerful forward genetics approach to dissect virus-host cell interactions. Here we report the identification of 305 host proteins that affect WNV infection, using a human-genome-wide RNAi screen. Functional clustering of the genes revealed a complex dependence of this virus on host cell physiology, requiring a wide variety of molecules and cellular pathways for successful infection. We further demonstrate a requirement for the ubiquitin ligase CBLL1 in WNV internalization, a post-entry role for the endoplasmic-reticulum-associated degradation pathway in viral infection, and the monocarboxylic acid transporter MCT4 as a viral replication resistance factor. By extending this study to dengue virus, we show that flaviviruses have both overlapping and unique interaction strategies with host cells. This study provides a comprehensive molecular portrait of WNV-human cell interactions that forms a model for understanding single plus-stranded RNA virus infection, and reveals potential antiviral targets.

PMID: 18690214 [PubMed - indexed for MEDLINE]

8: J Exp Med. 2008 Aug 4;205(8):1929-38. Epub 2008 Jul 28.

http://www.ncbi.nlm.nih.gov/pubmed/18663127

Transcriptional role of p53 in interferon-mediated antiviral immunity.

Muñoz-Fontela C, Macip S, Martínez-Sobrido L, Brown L, Ashour J, García-Sastre A, Lee SW, Aaronson SA.

Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, USA.

Tumor suppressor p53 is activated by several stimuli, including DNA damage and oncogenic stress. Previous studies (Takaoka, A., S. Hayakawa, H. Yanai, D. Stoiber, H. Negishi, H. Kikuchi, S. Sasaki, K. Imai, T. Shibue, K. Honda, and T. Taniguchi. 2003. Nature. 424:516-523) have shown that p53 is also induced in response to viral infections as a downstream transcriptional target of type I interferon (IFN) signaling. Moreover, many viruses, including SV40, human papillomavirus, Kaposi's sarcoma herpesvirus, adenoviruses, and even RNA viruses such as polioviruses, have evolved mechanisms designated to abrogate p53 responses. We describe a novel p53 function in the activation of the IFN pathway. We observed that infected mouse and human cells with functional p53 exhibited markedly decreased viral replication early after infection. This early inhibition of viral replication was mediated both in vitro and in vivo by a p53-dependent enhancement of IFN signaling, specifically the induction of genes containing IFN-stimulated response elements. Of note, p53 also contributed to an increase in IFN release from infected cells. We established that this p53-dependent enhancement of IFN signaling is dependent to a great extent on the ability of p53 to activate the transcription of IFN regulatory factor 9, a central component of the IFN-stimulated gene factor 3 complex. Our results demonstrate that p53 contributes to innate immunity by enhancing IFN-dependent antiviral activity independent of its functions as a proapoptotic and tumor suppressor gene.

PMID: 18663127 [PubMed - indexed for MEDLINE]

9. Science 4 September 2009: Vol. 325. no. 5945, pp. 1265 - 1269

DOI: 10.1126/science.1175455

http://www.ebioscience.com/ebioscience/specs/antibody_25/25-5790.htm

Recruitment of Antigen-Specific CD8+ T Cells in Response to Infection Is Markedly Efficient

Jeroen W. J. van Heijst,1 Carmen Gerlach,1 Erwin Swart,1 Daoud Sie,2 Cláudio Nunes-Alves,3 Ron M. Kerkhoven,2 Ramon Arens,1,* Margarida Correia-Neves,3 Koen Schepers,1,  Ton N. M. Schumacher1,

The magnitude of antigen-specific CD8+ T cell responses is not fixed but correlates with the severity of infection. Although by definition T cell response size is the product of both the capacity to recruit naïve T cells (clonal selection) and their subsequent proliferation (clonal expansion), it remains undefined how these two factors regulate antigen-specific T cell responses. We determined the relative contribution of recruitment and expansion by labeling naïve T cells with unique genetic tags and transferring them into mice. Under disparate infection conditions with different pathogens and doses, recruitment of antigen-specific T cells was near constant and close to complete. Thus, naïve T cell recruitment is highly efficient, and the magnitude of antigen-specific CD8+ T cell responses is primarily controlled by clonal expansion.

10.  Published online August 31, 2009

doi:10.1083/jcb.200906110

The Journal of Cell Biology

http://jcb.rupress.org/cgi/content/full/jcb.200906110v1?ijkey=6a0c46d2d85ffc0171f8d157cfd103311dcda1f2

The TRC8 E3 ligase ubiquitinates MHC class I molecules before dislocation from the ER

Helen R. Stagg, Mair Thomas, Dick van den Boomen, Emmanuel J.H.J. Wiertz, Harry A. Drabkin, Robert M. Gemmill, and Paul J. Lehner

The US2 and US11 gene products of human cytomegalovirus promote viral evasion by hijacking the endoplasmic reticulum (ER)–associated degradation (ERAD) pathway. US2 and US11 initiate dislocation of newly translocated major histocompatibility complex class I (MHC I) from the ER to the cytosol for proteasome-mediated degradation, thereby decreasing cell surface MHC I. Despite being instrumental in elucidating the mammalian ERAD pathway, the responsible E3 ligase or ligases remain unknown. Using a functional small interfering RNA library screen, we now identify TRC8 (translocation in renal carcinoma, chromosome 8 gene), an ER-resident E3 ligase previously implicated as a hereditary kidney cancer gene, as required for US2-mediated MHC I ubiquitination. Depletion of TRC8 prevents MHC I ubiquitination and dislocation by US2 and restores cell surface MHC I. TRC8 forms an integral part of a novel multiprotein ER complex that contains MHC I, US2, and signal peptide peptidase. Our data show that the TRC8 E3 ligase is required for MHC I dislocation from the ER and identify a new complex associated with mammalian ERAD.

Commented on:

Cytomegalovirus sticks it to MHC

     Mitch Leslie

     J. Cell Biol. published 31 August 2009, 10.1083/jcb.1865iti1

     http://jcb.rupress.org/cgi/content/full/jcb.1865iti1v1?ct