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Unexpected positive control of NF?B and miR-155 by DGK? and ? ensures effector and memory CD8+ T cell differentiation.

ABSTRACT: Signals from the T-cell receptor (TCR) and ?-chain cytokine receptors play crucial roles in initiating activation and effector/memory differentiation of CD8 T-cells. We report here that simultaneous deletion of both diacylglycerol kinase (DGK) ? and ? (DKO) severely impaired expansion of CD8 effector T cells and formation of memory CD8 T-cells after Listeria monocytogenes infection. Moreover, ablation of both DGK? and ? in preformed memory CD8 T-cells triggered death and impaired homeostatic proliferation of these cells. DKO CD8 T-cells were impaired in priming due to decreased expression of chemokine receptors and migration to the draining lymph nodes. Moreover, DKO CD8 T-cells were unexpectedly defective in NF?B-mediated miR-155 transcript, leading to excessive SOCS1 expression and impaired ?-chain cytokine signaling. Our data identified a DGK-NF?B-miR-155-SOCS1 axis that bridges TCR and ?-chain cytokine signaling for robust CD8 T-cell primary and memory responses to bacterial infection.

SUBMITTER: Yang J

PROVIDER: S-EPMC5085116 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation.

Yang Jialong J Zhang Ping P Krishna Sruti S Wang Jinli J Lin Xingguang X Huang Hongxiang H Xie Danli D Gorentla Balachandra B Huang Rick R Gao Jimin J Li Qi-Jing QJ Zhong Xiao-Ping XP

Oncotarget 20160601 23

Signals from the T-cell receptor (TCR) and γ-chain cytokine receptors play crucial roles in initiating activation and effector/memory differentiation of CD8 T-cells. We report here that simultaneous deletion of both diacylglycerol kinase (DGK) α and ζ (DKO) severely impaired expansion of CD8 effector T cells and formation of memory CD8 T-cells after Listeria monocytogenes infection. Moreover, ablation of both DGKα and ζ in preformed memory CD8 T-cells triggered death and impaired homeostatic pro ...[more]

PMID: 27014906

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Project description:BackgroundBrain inflammation is a key cause of cognitive decline after central nervous system (CNS) infections. A thorough understanding of immune responses to CNS infection is essential for developing anti-inflammatory interventions that improve outcomes. Tissue-resident memory T cells (TRM) are non-recirculating memory T cells that provide surveillance of previously infected tissues. However, in addition to protecting the brain against reinfection, brain TRM can contribute to post-infectious neuroinflammation. We hypothesized that accumulation of CD8+ TRM in the brain could be reduced by inhibiting microRNA (miR)-155, a microRNA that influences development of cytotoxic CD8+ T lymphocytes during infection.MethodsC57BL/6J mice were infected by intraperitoneal injection with a lethal inoculum of Listeria monocytogenes (Lm) then treated with antibiotics. Flow cytometry was used to quantify specific populations of brain leukocytes 28-29 days (d) post-infection (p.i.). To test the degree to which miR-155 altered leukocyte influxes into the brain, infected mice were injected with a miR-155 inhibitor or locked nucleic acid (LNA) scramble control 2d, 4d, 6d, and 8d p.i. along with antibiotic treatment. Bacterial loads in spleen and liver and body weights were measured up to 7d p.i. Brain leukocytes were analyzed 14d and 28d p.i. Confirmatory studies were performed in mutated mice lacking miR-155 (miR-155-/-) RESULTS: Lm infection significantly increased the numbers of brain CD3+CD8+ lymphocytes at 28d p.i. These cells were extravascular, and displayed markers characteristic of TRM, with the predominant phenotype of CD44+CD62L-CD69+CX3CR1-. Further analysis showed that > 75% of brain TRM also expressed CD49a, PD-1, Ly6C, CD103, and CD127. Mice injected with miR-155 inhibitor lost less weight through 7d p.i. than did control mice, whereas bacterial loads in brain, liver, and spleen were not different from controls. By 28d p.i., the numbers of brain CD8+ TRM cells were significantly decreased in mice treated with the inhibitor compared with controls. Similarly, miR-155-/- mice showed significantly reduced numbers of brain CD8+ TRM cells by 28d p.i.ConclusionsBrain CD8+ TRM populations are established during neuroinvasive Lm infection. Accumulation of brain CD8+ TRM cells is reduced by blocking miR-155 and in miR-155-/- mice, indicating that this molecule has a critical role in development of these specialized cells. Administering anti-miR-155 during infection could provide a novel avenue for reducing post-infectious neuroinflammation.

Project description:Memory CD8 T cells that circulate in the blood and are present in lymphoid organs are an essential component of long-lived T cell immunity. These memory CD8 T cells remain poised to rapidly elaborate effector functions upon re-exposure to pathogens, but also have many properties in common with naive cells, including pluripotency and the ability to migrate to the lymph nodes and spleen. Thus, memory cells embody features of both naive and effector cells, fuelling a long-standing debate centred on whether memory T cells develop from effector cells or directly from naive cells. Here we show that long-lived memory CD8 T cells are derived from a subset of effector T cells through a process of dedifferentiation. To assess the developmental origin of memory CD8 T cells, we investigated changes in DNA methylation programming at naive and effector cell-associated genes in virus-specific CD8 T cells during acute lymphocytic choriomeningitis virus infection in mice. Methylation profiling of terminal effector versus memory-precursor CD8 T cell subsets showed that, rather than retaining a naive epigenetic state, the subset of cells that gives rise to memory cells acquired de novo DNA methylation programs at naive-associated genes and became demethylated at the loci of classically defined effector molecules. Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells. Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naive-associated genes. Thus, epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fate-permissive effector T cells.

Dataset Information

Unexpected positive control of NF?B and miR-155 by DGK? and ? ensures effector and memory CD8+ T cell differentiation.

Publications

Unexpected positive control of NFκB and miR-155 by DGKα and ζ ensures effector and memory CD8+ T cell differentiation.

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