Editorial GuideImmunology

Focus Issue: External and Internal Regulators of Immune Responses

Sci. Signal.  19 Jan 2010:
Vol. 3, Issue 105, pp. eg2
DOI: 10.1126/scisignal.3105eg2


This Focus Issue of Science Signaling, which complements the Science Special Issue on Innate Immunity (http://www.sciencemag.org/special/immunity), highlights the effects of viral and bacterial components on host cells, signaling pathways involved in regulating innate immune responses, and factors that modulate the functions of dendritic cells, which are required for effective adaptive immunity.

From tiny viruses to large parasites, invading pathogens and their hosts have developed a complex interaction in which the pathogen strives to survive, replicate, and infect more cells of the host, and the host tries to eliminate infected cells and the invading pathogen. The innate and adaptive immune responses play critical roles in the host response to pathogens; however, factors associated with the invading organism or the infected host cells modulate the immune response, influencing disease progression. Pathogen-associated factors and host-derived components are recognized by host receptors at the surface of cells, within intracellular compartments, or located in the cytosol. Recognition of pathogen- or host-derived factors triggers signaling pathways that affect the outcome of infection, determining such events as which types of cytokines and chemokines are produced by the host as it mounts an immune response and whether the infected cell survives or dies quickly. Such outcomes also have ramifications for the invading organism as it tries to optimize conditions for its own replication and ability to spread and infect more cells. A series of complementary articles at Science and Science Signaling highlights the effects of pathogen-derived and host-produced factors on the immune response.

Viruses, bacteria, and parasites all produce proteins that can interact with host cell proteins to modify the host cell's behavior. In a Research Article in this Focus Issue, Préhaud et al. compared an attenuated strain of rabies virus to a virulent strain and demonstrated that a single amino acid change in the envelope glycoprotein (G) of the virus was sufficient to determine whether the infected cells survived or died. Other Research Articles in the Archives also highlight the importance of interactions between components of host cells and invading organisms for the outcome of infection. Chuenkova and PereiraPerrin showed how a surface protein of the intracellular parasite Trypansoma cruzi, the causative agent of Chagas’ disease, acts both extracellularly during the process of infection and intracellularly within the infected cell to trigger the activation of the host kinase Akt. This dual mechanism of activating Akt ensures that the host cell survives long enough for the parasite to replicate and infect other cells. Gomez et al. demonstrated that GP63, a surface glycoprotein of the parasite Leishmania, causes the cleavage and activation of host protein tyrosine phosphatases to promote infection. Finally, in a twist in the host-versus-microbe scenario, Christen et al. showed that rather than affecting the activity of a host protein, the Salmonella virulence factor SseJ instead binds to and is itself activated by the active form of the host guanosine triphosphatase (GTPase) RhoA.

Proteins are not the only pathogen-associated components important in the host-pathogen interaction. Host cells have developed intricate mechanisms for detecting various pathogen-associated molecules or patterns. In a Perspective in Science, Rehwinkel and Reis e Sousa describe the host's cellular machinery that is required to sense and respond to viral RNAs. These nucleic acids bind to pathogen recognition receptors (PRRs) of the retinoic acid–inducible gene I (RIG-I)–like receptor (RLR) family, in particular RIG-I and melanoma differentiation–associated gene 5 (MDA5). Upon binding to viral RNAs, RIG-I and MDA5 bind to the outer mitochondrial membrane adaptor protein MAVS [for mitochondrial antiviral signaling, also known as IPS-1, VISA, and CARDIF] through homotypic interactions between caspase-recruitment domains (CARDs) on each protein. MAVS, in turn, activates downstream kinases to induce the expression of genes encoding the type I interferons (IFNs), the main effectors in the antiviral response. As Rehwinkel and Reis e Sousa discuss, the effectiveness of the RLR proteins depends on their exquisite ability to differentiate between RNAs endogenous to the host and those that come from, or are generated in response to, infecting viruses. As part of the ever-escalating war between viruses and the immune systems of their target organisms, various viruses have adopted strategies to interfere with these receptors. In Perspectives in the Archives, Vitour and Meurs outline how RIG-I and LGP2, another RLR, regulate the production of IFN, and Wegener and Krappmann discuss how signalosomes that consist of different CARD-containing proteins link various cell-surface receptors to the activation of the transcription factor nuclear factor κB (NF-κB), which is required for a proinflammatory response.

Nucleotide-binding oligomerization domain (NOD)–like receptor (NLR) family proteins [also known as nucleotide-binding domain (NBD), leucine-rich repeat (LRR)–containing receptors] are another type of host protein that recognizes pathogen-derived molecules called pathogen-associated molecular patterns (PAMPs), as well as host-derived molecules called damage-associated molecular patterns (DAMPs). NLRs trigger the activation of mitogen-activated protein kinases (MAPKs) and NF-κB, and they stimulate the production of proinflammatory cytokines and chemokines. Not only do animal cells rely on NLR proteins for responding to infection, but NLR family members, such as the resistance (R) proteins, are critical for the responses of plants to infections, which is the subject of a Perspective by Burch-Smith and Dinesh-Kumar in the Archives.

NLRs either can function as part of complexes known as inflammasomes or can interact with other proteins and function independently from inflammasomes. Inflammasome-independent functions of NLRs are highlighted in the Science Review by Ting et al. that focuses on particular NLR proteins and their interaction with components of the mitochondrial-associated antiviral machinery, such as MAVS and RIG-I. Ting et al. also describe the inhibitory processes that limit the activity of MAVS. One such mechanism was shown in a Research Article by Yasukawa et al. in the Archives, in which they demonstrated that the mitochondrial fusion protein mitofusin 2 (Mfn2) associates with MAVS in a CARD-independent manner to prevent its interaction with, and activation by, RIG-I.

When functioning as part of the inflammasome, NLR proteins serve as molecular sensors for these cytosolic, multiprotein complexes that stimulate caspase-1 to process the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The processing of IL-1β by an inflammasome that contains the NLR protein NLRP3 (also known as NALP3) is described in one of a pair of interconnected Connections Maps pathways by Weber et al. in this issue. In a Review in Science, Schroder et al. discuss a role for the NLRP3 inflammasome in the development of type 2 diabetes mellitus and suggest that the NLRP3 inflammasome acts as a sensor of metabolic stress and processes IL-1β, which has a pathogenic role in the destruction of pancreatic β cells.

The mechanism of action of IL-1β is the subject of a second Connections Map pathway and associated Overview by Weber et al. in this issue. In addition to outlining the cellular response to IL-1β, the Connections Map includes the multiple levels of regulation of IL-1β signaling, which are critical for controlling signaling by this proinflammatory mediator. IL-1β signaling leads to the activation of NF-κB through a mechanism that depends on the E3 ubiquitin ligase and scaffolding protein tumor necrosis factor (TNF) receptor–associated factor 6 (TRAF6). In a Perspective in this issue, Wuerzberger-Davis and Miyamoto highlight the work of Yamazaki et al., which showed that IL-1 signaling activates NF-κB through two mechanistically and temporally distinct pathways that diverge at TRAF6 and that are both important for a prolonged proinflammatory response.

Like the NLRs and RLRs, Toll-like receptors (TLRs) are another flavor of PRR. In a Science Review, Iwasaki and Medzhitov discuss the relative contributions of all three types of PRR—NLRs, RLRs, and TLRs—to immune responses. In addition to their long-standing role in innate immunity, roles for TLRs in adaptive immunity are also emerging. For example, the uptake of antigen by dendritic cells (DCs) in the context of TLR stimulation has profound effects on the responses of the T cells to which the antigen is presented by the DCs. For an overview of TLR signaling, see the Review by Dunne and O’Neill in the Archives and the TLR Pathway in the Database of Cell Signaling.

The presentation of antigen to T cells by DCs occurs during the formation of an immunological synapse at the point of contact between the T cell and the DC (see the Perspective by Varma in the Archives). Because of the importance of the immunological synapse for the proper activation of T cells, many studies, including Research Articles in the Archives, have focused on the T cell side of the immunological synapse and investigated signaling by the T cell receptor (TCR) complex. Mayya et al. performed a quantitative, mass spectrometry–based analysis of TCR signaling in Jurkat T cells and found a large contribution of phosphorylated Ser and Thr residues (in addition to the more widely studied Tyr residues) in mediating protein-protein interactions. Singleton et al. used tagged proteins and fluorescence microscopy techniques to visualize the spatiotemporal patterning of some 30 signaling components during TCR signaling. For other insights into how ever-improving visualization tools have expanded our knowledge of immune responses, see the Meeting Report by Dustin in the Archives. Martínez-Martín et al. investigated the role of the ε subunit of CD3, part of the TCR complex, in transducing the effects of antigen-binding to the inside of the T cell. In terms of molecules that are recruited to the TCR complex, Saveliev et al. showed that only some of the functions of the guanine nucleotide exchange factor (GEF) Vav1 in mediating TCR signaling depend on its GEF activity, and Patsoukis et al. demonstrated that the adaptor molecule RIAM, which interacts with and contributes to the activation of integrins in response to stimulation of the TCR (a late-stage response), was also recruited to the TCR complex to participate in the early stages of TCR signaling.

Relatively few studies, however, have investigated the events that occur on the DC side of the immunological synapse, which is the subject of a Review by Rodríguez-Fernández et al. in this issue. In particular, the authors discuss some of the signaling molecules in DCs that are recruited to the immunological synapse and may be involved in enhancing the survival of DCs during their interactions with target T cells. Finally, one of the important functions of the immunological synapse is to ensure the localized distribution of cytokines between DCs and T cells. Cytokines released by DCs govern the differentiation pathways followed by activated T cells. For example, the DC-derived cytokine IL-12 drives the differentiation of T helper type I (TH1) T cells, which are important for immune responses against intracellular pathogens, whereas IL-4 signaling, the subject of a Research Article by Heller et al. and a Perspective by Wills-Karp and Finkelman in the Archives, drives the differentiation of TH2 cells, which are important in allergy and for responses to extracellular parasites. In a Research Article in this issue, Arima et al. investigated the response of human myeloid DCs to thymic stromal lymphopoietin (TSLP), a cytokine associated with TH2-type responses. The authors showed that TSLP induced a set of signals distinct from those triggered by other activators of DCs, such as TLR ligands, which not only induced the activation of TH2-associated transcription factors but also limited the activation of factors required by DCs to drive TH1-type responses.

A common thread that connects the articles featured in this Focus Issue is the importance of inflammatory modulators produced by the host and pathogen-derived components that influence the host response to infection. We hope that, by highlighting these articles, we will have piqued your interest in investigating other signaling pathways that regulate host defense.

Featured in This Focus Issue

Research Articles

  • K. Arima, N. Watanabe, S. Hanabuchi, M. Chang, S.-C. Sun, Y.-J. Liu, Distinct signal codes generate dendritic cell functional plasticity. Sci. Signal. 3, ra4 (2010). [Abstract] [Full Text] [PDF]

  • C. Préhaud, N. Wolff, E. Terrien, M. Lafage, F. Mégret, N. Babault, F. Cordier, G. S. Tan, E. Maitrepierre, P. Ménager, D. Chopy, S. Hoos, P. England, M. Delepierre, M. J. Schnell, H. Buc, M. Lafon, Attenuation of rabies virulence: Takeover by the cytoplasmic domain of its envelope protein. Sci. Signal. 3, ra5 (2010). [Abstract] [Full Text] [PDF]


  • S. M. Wuerzberger-Davis, S. Miyamoto, TAK-ling IKK activation: “Ub” the judge. Sci. Signal. 3, pe3 (2010). [Abstract] [Full Text] [PDF]


  • J. L. Rodríguez-Fernández, L. Riol-Blanco, C. Delgado-Martín, What is the function of the dendritic cell side of the immunological synapse? Sci. Signal. 3, re2 (2010). [Abstract] [Full Text] [PDF]


  • A. Weber, P. Wasiliew, M. Kracht, Interleukin-1 (IL-1) Pathway. Sci. Signal. (Connections Map Pathway in the Database of Cell Signaling, as seen January 2010), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_21286. [Abstract] [Full Text] [PDF] [About Connections Map]

  • A. Weber, P. Wasiliew, M. Kracht, Interleukin-1β (IL-1β) Processing Pathway. Sci. Signal. (Connections Map Pathway in the Database of Cell Signaling, as seen January 2010), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_21962. [Abstract] [Full Text] [PDF] [About Connections Map]

Virtual Journal

  • A. Iwasaki, R. Medzhitov, Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010). [Abstract] [Full Text] [PDF]

  • J. Rehwinkel, C. Reis e Sousa, RIGorous detection: Exposing virus through RNA sensing. Science 327, 284–286 (2010). [Abstract] [Full Text] [PDF]

  • J. P. Y. Ting, J. A. Duncan, Y. Lei, How the noninflammasome NLRs function in the innate immune system. Science 327, 286–290 (2010). [Abstract] [Full Text] [PDF]

  • K. Schroder, R. Zhou, J. Tschopp, The NLRP3 inflammasome: A sensor for metabolic danger? Science 327, 296–300 (2010). [Abstract] [Full Text] [PDF]

Related Resources

Research Articles

  • M. Christen, L. H. Coye, J. S. Hontz, D. L. LaRock, R. A. Pfuetzner, Megha, S. I. Miller, Activation of a bacterial virulence protein by the GTPase RhoA. Sci. Signal. 2, ra71 (2009). [Abstract] [Full Text] [PDF]

  • M. V. Chuenkova, M. PereiraPerrin, Trypanosoma cruzi targets Akt in host cells as an intracellular antiapoptotic strategy. Sci. Signal. 2, ra74 (2009). [Abstract] [Full Text] [PDF]

  • M. A. Gomez, I. Contreras, M. Hallé, M. L. Tremblay, R. W. McMaster, M. Olivier, Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases. Sci. Signal. 2, ra58 (2009). [Abstract] [Full Text] [PDF]

  • N. M. Heller, X. Qi, I. S. Junttila, K. A. Shirey, S. N. Vogel, W. E. Paul, A. D. Keegan, Type I IL-4Rs selectively activate IRS-2 to induce target gene expression in macrophages. Sci. Signal. 1, ra17 (2008). [Abstract] [Full Text] [PDF]

  • N. Martínez-Martín, R. M. Risueño, A. Morreale, I. Zaldívar, E. Fernández-Arenas, F. Herranz, A. R. Ortiz, B. Alarcón, Cooperativity between T cell receptor complexes revealed by conformational mutants of CD3ε. Sci. Signal. 2, ra43 (2009). [Abstract] [Full Text] [PDF]

  • V. Mayya, D. H. Lundgren, S.-I. Hwang, K. Rezaul, L. Wu, J. K. Eng, V. Rodionov, D. K. Han, Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci. Signal. 2, ra46 (2009). [Abstract] [Full Text] [PDF]

  • N. Patsoukis, E. M. Lafuente, P. Meraner, J. s. Kim, D. Dombkowski, L. Li, V. A. Boussiotis, RIAM regulates the cytoskeletal distribution and activation of PLC-γ1 in T cells. Sci. Signal. 2, ra79 (2009). [Abstract] [Full Text] [PDF]

  • A. Saveliev, L. Vanes, O. Ksionda, J. Rapley, S. J. Smerdon, K. Rittinger, V. L. J. Tybulewicz, Function of the nucleotide exchange activity of Vav1 in T cell development and activation. Sci. Signal. 2, ra83 (2009). [Abstract] [Full Text] [PDF]

  • K. L. Singleton, K. T. Roybal, Y. Sun, G. Fu, N. R. J. Gascoigne, N. S. C. van Oers, C. Wülfing, Spatiotemporal patterning during T cell activation is highly diverse. Sci. Signal. 2, ra15 (2009). [Abstract] [Full Text] [PDF]

  • K. Yamazaki, J. Gohda, A. Kanayama, Y. Miyamoto, H. Sakurai, M. Yamamoto, S. Akira, H. Hayashi, B. Su, J.-i. Inoue, Two mechanistically and temporally distinct NF-κB activation pathways in IL-1 signaling. Sci. Signal. 2, ra66 (2009). [Abstract] [Full Text] [PDF]

  • K. Yasukawa, H. Oshiumi, M. Takeda, N. Ishihara, Y. Yanagi, T. Seya, S.-i. Kawabata, T. Koshiba, Mitofusin 2 inhibits mitochondrial antiviral signaling. Sci. Signal. 2, ra47 (2009). [Abstract] [Full Text] [PDF]

Editorial Guides

  • J. F. Foley, E. M Adler, Focus Issue: Uncovering immunological secrets. Sci. STKE 2007, eg7 (2007). [Abstract] [Full Text] [PDF]

  • J. F. Foley, E. M Adler, N. R. Gough, Focus Issue: Keeping the immune response in check. Sci. STKE 2007, eg4 (2007). [Abstract] [Full Text] [PDF]


  • A. Dunne, L. A. J. O'Neill, The interleukin-1 receptor/Toll-like receptor superfamily: Signal transduction during inflammation and host defense. Sci. STKE 2003, re3 (2003). [Abstract] [Full Text] [PDF]


  • T. M. Burch-Smith, S. P. Dinesh-Kumar, The functions of plant TIR domains. Sci. STKE 2007, pe46 (2007). [Abstract] [Full Text] [PDF]

  • R. Varma, TCR triggering by the pMHC complex: Valency, affinity, and dynamics. Sci. Signal. 1, pe21 (2008). [Abstract] [Full Text] [PDF]

  • D. Vitour, E. F. Meurs, Regulation of interferon production by RIG-I and LGP2: A lesson in self-control. Sci. STKE 2007, pe20 (2007). [Abstract] [Full Text] [PDF]

  • E. Wegener, D. Krappmann, CARD-Bcl10-Malt1 signalosomes: Missing link to NF-κB. Sci. STKE 2007, pe21 (2007). [Abstract] [Full Text] [PDF]

  • M. Wills-Karp, F. D. Finkelman, Untangling the complex web of IL-4– and IL-13–mediated signaling pathways. Sci. Signal. 1, pe55 (2008). [Abstract] [Full Text] [PDF]

Meeting Report

  • M. L. Dustin, Visualizing immune system complexity. Sci. Signal. 2, mr4 (2009). [Abstract] [Full Text] [PDF]


  • G. M. Barton, R. Medzhitov, Toll-like receptor pathway. Sci. Signal. (Connections Map Pathway in the Database of Cell Signaling, as seen January 2010), http://stke.sciencemag.org/cgi/cm/stkecm;CMP_8643. [About Connections Map]

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