Dataset Information

Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.

ABSTRACT: TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. gondii profilin and are capable of forming a heterodimer complex. We also establish that the transcription factor IFN regulatory factor 8, not NF-?B, plays a central role in the regulation of the TLR11- and TLR12-dependent IL-12 response of DCs. These results suggest a central role for IFN regulatory factor 8-expressing CD8(+) DCs in governing the TLR11- and TLR12-mediated host defense against T. gondii.

SUBMITTER: Raetz M

PROVIDER: S-EPMC3805684 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Publications

Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.

Raetz Megan M Kibardin Alexey A Sturge Carolyn R CR Pifer Reed R Li Haiying H Burstein Ezra E Ozato Keiko K Larin Sergey S Yarovinsky Felix F

Journal of immunology (Baltimore, Md. : 1950) 20130927 9

TLRs play a central role in the innate recognition of pathogens and the activation of dendritic cells (DCs). In this study, we establish that, in addition to TLR11, TLR12 recognizes the profilin protein of the protozoan parasite Toxoplasma gondii and regulates IL-12 production by DCs in response to the parasite. Similar to TLR11, TLR12 is an endolysosomal innate immune receptor that colocalizes and interacts with UNC93B1. Biochemical experiments revealed that TLR11 and TLR12 directly bind to T. ...[more]

PMID: 24078692

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Project description:CD8(+) T cells play an essential role in the protection against both acute as well as chronic Toxoplasma gondii infection. Although the role of IL-15 has been reported to be important for the development of long-term CD8(+) T cell immunity against the pathogen, the simultaneous roles played by both IL-15 and related gamma-chain family cytokine IL-7 in the generation of this response during acute phase of infection has not been described. We demonstrate that while lack of IL-7 or IL-15 alone has minimal impact on splenic CD8(+) T cell maturation or effector function development during acute Toxoplasmosis, absence of both IL-7 and IL-15 only in the context of infection severely down-regulates the development of a potent CD8(+) T cell response. This impairment is characterized by reduction in CD44 expression, IFN-gamma production, proliferation and cytotoxicity. However, attenuated maturation and decreased effector functions in these mice are essentially downstream consequences of reduced number of antigen-specific CD8(+) T cells. Interestingly, the absence of both cytokines did not impair initial CD8(+) T cell generation but affected their survival and differentiation into memory phenotype IL-7Ralpha(hi) cells. Significantly lack of both cytokines severely affected expression of Bcl-2, an anti-apoptotic protein, but minimally affected proliferation. The overarching role played by these cytokines in eliciting a potent CD8(+) T cell immunity against T. gondii infection is further evidenced by poor survival and high parasite burden in anti IL-7 treated IL-15(-/-) mice. These studies demonstrate that the two cytokines, IL-7 and IL-15, are exclusively important for the development of protective CD8(+) T cell immune response against T. gondii. To the best of our knowledge this synergism between IL-7 and IL-15 in generating an optimal CD8(+) T cell immunity against intracellular parasite or any other infectious disease model has not been previously reported.

Dataset Information

Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.

Publications

Cooperation of TLR12 and TLR11 in the IRF8-dependent IL-12 response to Toxoplasma gondii profilin.

Similar Datasets

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