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Essential role of I?B_NS for in vivo CD4⁺ T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

ABSTRACT: Acquisition of effector functions in T cells is guided by transcription factors, including NF-?B, that itself is tightly controlled by inhibitory proteins. The atypical NF-?B inhibitor, I?B_NS, is involved in the development of Th1, Th17, and regulatory T (Treg) cells. However, it remained unclear to which extend I?B_NS contributed to the acquisition of effector function in T cells specifically responding to a pathogen during in vivo infection. Tracking of adoptively transferred T cells in Listeria monocytogenes infected mice antigen-specific activation of CD4⁺ T cells following in vivo pathogen encounter to strongly rely on I?B_NS . While I?B_NS was largely dispensable for the acquisition of cytotoxic effector function in CD8⁺ T cells, I?B_NS -deficient Th1 effector cells exhibited significantly reduced proliferation, marked changes in the pattern of activation marker expression, and reduced production of the Th1-cell cytokines IFN-?, IL-2, and TNF-?. Complementary in vitro analyses using cells from novel reporter and inducible knockout mice revealed that I?B_NS predominantly affects the early phase of Th1-cell differentiation while its function in terminally differentiated cells appears to be negligible. Our data suggest I?B_NS as a potential target to modulate specifically CD4⁺ T-cell responses.

SUBMITTER: Frentzel S

PROVIDER: S-EPMC6771600 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Essential role of IκBNS for in vivo CD4+ T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

Frentzel Sarah S Katsoulis-Dimitriou Konstantinos K Jeron Andreas A Schmitz Ingo I Bruder Dunja D

European journal of immunology 20190607 9

Acquisition of effector functions in T cells is guided by transcription factors, including NF-κB, that itself is tightly controlled by inhibitory proteins. The atypical NF-κB inhibitor, IκBNS, is involved in the development of Th1, Th17, and regulatory T (Treg) cells. However, it remained unclear to which extend IκBNS contributed to the acquisition of effector function in T cells specifically responding to a pathogen during in vivo infection. Tracking of adoptively transfer ...[more]

PMID: 31049948

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Project description:IκB proteins regulate the inhibition and activation of NF-κB transcription factor complexes. While classical IκB proteins keep NF-κB complexes inactive in the cytoplasm, atypical IκB proteins act on activated NF-κB complexes located in the nucleus. Most of the knowledge regarding the function of IκB proteins has been collected in vitro, while far less is known regarding their impact on activation and regulation of immune responses during in vivo infections. Combining in vivo Listeria monocytogenes (Lm) infection with comparative ex vivo transcriptional profiling of the hepatic response to the pathogen we observed that in contrast to wild type mice that mounted a robust inflammatory response, IκBNS-deficiency was generally associated with a transcriptional repression of innate immune responses. Whole tissue transcriptomics revealed a pronounced IκBNS-dependent reduction of myeloid cell-associated transcripts in the liver together with an exceptionally high Nfkbid promoter activity uncovered in Ly6Chigh inflammatory monocytes prompted us to further characterize the specific contribution of IκBNS in the inflammatory response of monocytes to the infectious agent. Indeed, Ly6Chigh monocytes primed during Lm infection in the absence of IκBNS displayed a blunted response compared to wild type-derived Ly6Chigh monocytes as evidenced by the reduced early expression of hallmark transcripts of monocyte-driven inflammation such as Il6, Nos2 and Il1β. Strikingly, altered monocyte activation in IκBNS-deficient mice was associated with an exceptional resistance against Lm infection and protection was associated with a strong reduction in immunopathology in Lm target organs. Of note, mice lacking IκBNS exclusively in myeloid cells failed to resist Lm infection, indicating that the observed effect was not monocyte intrinsic but monocyte extrinsic. While serum cytokine-profiling did not discover obvious differences between wild type and IκBNS -/- mice for most of the analyzed mediators, IL-10 was virtually undetectable in IκBNS-deficient mice, both in the steady state and following Lm infection. Together, we show here a crucial role for IκBNS during Lm infection with IκBNS-deficient mice showing an overall blunted pro-inflammatory immune response attributed to a reduced pro-inflammatory signature in Ly6Chigh monocytes. Reduced immunopathology and complete protection of mice against an otherwise fatal Lm infection identified IκBNS as molecular driver of inflammation in listeriosis.

Dataset Information

Essential role of I?B_NS for in vivo CD4⁺ T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

Publications

Essential role of IκB<sub>NS</sub> for in vivo CD4<sup>+</sup> T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

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Dataset Information

Essential role of I?BNS for in vivo CD4+ T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

Publications

Essential role of IκB<sub>NS</sub> for in vivo CD4<sup>+</sup> T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Essential role of I?B_NS for in vivo CD4⁺ T-cell activation, proliferation, and Th1-cell differentiation during Listeria monocytogenes infection in mice.