A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity

Shaw, Michael H.; Boyartchuk, Victor L.; Wong, Sandy; Karaghiosoff, Marina; Ragimbeau, Josiane; Pellegrini, Sandra; Müller, Mathias; Dietrich, William F.; Yap, George

doi:10.1073/pnas.1930781100

Cited by 118 publications

(102 citation statements)

References 48 publications

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“…We further found that Tyk2 is critical for IL-17 production by ␥␦ T cells and protection against E. coli infection in vivo. There have been reports showing involvement of Tyk2 in IL-23-mediated signaling using Tyk2-deficient mice, including an impaired STAT3 phosphorylation of ConAstimulated T cells (13) and an impaired IFN-␥ production of dendritic cells (23). However, to our knowledge, this is the first report demonstrating an importance of Tyk2 in IL-23-mediated signaling for IL-17 production.…”

Section: Discussionmentioning

confidence: 72%

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Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by γδ T Cells

Nakamura

Shibata

Yamada

et al. 2008

The Journal of Immunology

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Tyrosine kinase 2 (Tyk2), a member of the JAK-signal transducer family, is involved in intracellular signaling triggered by various cytokines, including IL-23. We have recently reported that resident γδ T cells in the peritoneal cavity of naive mice produced IL-17 in response to IL-23. In this study, we examined importance of Tyk2-mediated signaling in the IL-17 production by γδ T cells using Tyk2 deficient (−/−) mice. γδ T cells in the peritoneal cavity of Tyk2−/− mice displayed effecter/memory phenotypes and TCR V repertoire similar to those in Tyk2+/+ mice and produced comparable level of IL-17 to those in Tyk2+/+ mice in response to PMA and ionomycin, indicating normal differentiation to IL-17-producing effectors in the absence of Tyk2-signaling. However, γδ T cells in Tyk2−/− mice produced less amount of IL-17 in response to IL-23 in vitro than those in Tyk2+/+ mice. Similarly, γδ T cells in the peritoneal cavity of Tyk2−/− mice showed severely impaired IL-17 production after an i.p. infection with E. coli despite comparable level of IL-23 production to Tyk2+/+ mice. As a consequence, Tyk2−/− mice showed a reduced infiltration of neutrophils and severely impaired bacterial clearance after Escherichia coli infection. These results indicate that Tyk2-signaling is critical for IL-23-induced IL-17 production by γδ T cells, which is involved in the first line of host defense by controlling neutrophil-mediated immune responses.

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Section: Discussionmentioning

confidence: 72%

“…As Tyk2 is recruited to IL-12R␤1 (9), IL-23-mediated signaling also likely involves Tyk2. In fact, an impaired IL-23-induced phosphorylation of STAT3 was shown in Tyk2-deficient T cells (13), suggesting an importance of Tyk2 for IL-23-mediated signaling for IL-17 production.…”

mentioning

confidence: 99%

Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by γδ T Cells

Nakamura

Shibata

Yamada

et al. 2008

The Journal of Immunology

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“…Recently, pseudokinases have emerged as key regulatory effectors in metazoan signal transduction (35), particularly in mammalian immune signaling (36,37). Although it is difficult to determine the specific role of a catalytically inactive protein, other pseudokinases have been shown to act as molecular scaffolds (38)(39)(40) and thereby, coordinate signal transduction.…”

Section: Discussionmentioning

confidence: 99%

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

Reese

Zeiner

Boothroyd

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

237

303

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Toxoplasma gondii, an obligate intracellular parasite of the phylum Apicomplexa, has the unusual ability to infect virtually any warm-blooded animal. It is an extraordinarily successful parasite, infecting an estimated 30% of humans worldwide. The outcome of Toxoplasma infection is highly dependent on allelic differences in the large number of effectors that the parasite secretes into the host cell. Here, we show that the largest determinant of the virulence difference between two of the most common strains of Toxoplasma is the ROP5 locus. This is an unusual segment of the Toxoplasma genome consisting of a family of 4-10 tandem, highly divergent genes encoding pseudokinases that are injected directly into host cells. Given their hypothesized catalytic inactivity, it is striking that deletion of the ROP5 cluster in a highly virulent strain caused a complete loss of virulence, showing that ROP5 proteins are, in fact, indispensable for Toxoplasma to cause disease in mice. We find that copy number at this locus varies among the three major Toxoplasma lineages and that extensive polymorphism is clustered into hotspots within the ROP5 pseudokinase domain. We propose that the ROP5 locus represents an unusual evolutionary strategy for sampling of sequence space in which the gene encoding an important enzyme has been (i) catalytically inactivated, (ii) expanded in number, and (iii) subject to strong positive selection. Such a strategy likely contributes to Toxoplasma's successful adaptation to a wide host range and has resulted in dramatic differences in virulence.copy number variation | host-pathogen interaction T he evolutionary pressure on the molecules that form the interface between a pathogenic organism and its host has been likened to an arms race (1, 2) and has been proposed to give rise to highly polymorphic genes such as those that encode host MHC and viral capsid proteins. Whereas most pathogens have a single or restricted range of hosts with which they coevolve, the obligate intracellular parasite Toxoplasma gondii can infect virtually any cell of almost any warm-blooded animal, a remarkable feat from an evolutionary perspective.Different strains of Toxoplasma cause significantly different disease in mice (3) and humans as well (4, 5). In North America and Europe, three strains have grown to dominate Toxoplasma's genetic landscape, and they are characterized by distinct disease outcomes in mice: although a single Type I parasite is uniformly lethal to a mouse, Type II and III parasites have a lethal dose (LD 50 ) ranging from 10 2 to 10 5 (3). Sexual crosses between members of these lineages (Type I × Type III and Type II × Type III) (6, 7) have shown that virulence in mice segregates among F1 progeny (8). This has allowed for the discovery of a number of virulence loci using quantitative trait loci (QTL) mapping (9, 10).Toxoplasma secretes an arsenal of effector proteins into its host cell from specialized secretory organelles termed rhoptries and dense granules (11)(12)(13)(14). Given the selective pressure...

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“…Interestingly, Tyk-2 is also involved in the function of several other cytokines that have been reported to be elevated in SLE patients, such as IL-6 and IL-10 (56). The importance of Tyk-2 in autoimmunity is further supported by the observation that Tyk-2-deficient mice are resistant to experimental arthritis (57). IRF-5, in contrast, is important for induction of IFN␣ production by viral infections and TLR-7/8 agonists and is constitutively expressed in NIPCs/PDCs (58,59).…”

Section: Introductionmentioning

confidence: 94%

The type I interferon system in systemic lupus erythematosus

Rönnblom

Eloranta

Alm

2006

Arthritis & Rheumatism

303

246

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A natural mutation in the Tyk2 pseudokinase domain underlies altered susceptibility of B10.Q/J mice to infection and autoimmunity

Abstract: The B10.Q͞J strain of mice was serendipitously discovered to be highly susceptible to infection by the intracellular protozoan parasite, Toxoplasma gondii but markedly resistant to induction of autoimmune arthritis. We have previously shown that the B10.

Cited by 118 publications

References 48 publications

Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by γδ T Cells

Tyk2-Signaling Plays an Important Role in Host Defense against Escherichia coli through IL-23-Induced IL-17 Production by γδ T Cells

Polymorphic family of injected pseudokinases is paramount in Toxoplasma virulence

The type I interferon system in systemic lupus erythematosus

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