Dataset Information

Keratinocyte-Mediated Activation of the Cytokine TGF-? Maintains Skin Recirculating Memory CD8+ T Cells.

ABSTRACT: Regulated activation of the cytokine TGF-? by integrins ?v?6 and ?v?8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking ?v?6 and ?v?8 integrins (Itgb6-/-Itgb8fl/fl-K14-cre), the absence of epidermal-activated TGF-? resulted in a gradual loss of E- or P-selectin-binding central and peripheral memory populations, which were rescued when skin entry was inhibited. Skin recirculating memory cells were required for optimal host defense against skin VV infection. These data demonstrate that skin migration can persist after resolution of local skin infection and that the cytokine environment within this nonlymphoid tissue shapes the differentiation state and persistence of the central and peripheral memory-T-cell pool.

SUBMITTER: Hirai T

PROVIDER: S-EPMC6531326 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Publications

Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8+ T Cells.

Hirai Toshiro T Zenke Yukari Y Yang Yi Y Bartholin Laurent L Beura Lalit K LK Masopust David D Kaplan Daniel H DH

Immunity 20190402 5

Regulated activation of the cytokine TGF-β by integrins αvβ6 and αvβ8 expressed on keratinocytes is required for residence of epidermal-resident memory T cells, but whether skin-derived signals also affect recirculating memory cells in the skin remains unclear. Here, we show that after resolution of skin vaccinia virus (VV) infection, antigen-specific circulating memory CD8+ T cells migrated into skin. In mice lacking αvβ6</s ...[more]

PMID: 30952606

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Project description:BackgroundNorepinephrine (NE) is one of the primary catecholamines of the sympathetic nervous system released during a stress response and plays an important role in modulating immune function. NE binds to the adrenergic receptors on immune cells, including T cells, resulting in either suppressed or enhanced function depending on the type of cell, activation status of the cell, duration of NE exposure and concentration of NE. Here, we aim to analyze the effects of NE on the functionality of naïve (Tn), central memory (Tcm) and effector memory (Tem) CD8 T cells.MethodsWe isolated CD8 T cell subsets from healthy human adults and treated cells in vitro with NE (1×10(-6)M) for 16h; we then stimulated NE treated and untreated CD8 T cell subsets with antibodies for CD3 and CD28 for 24 and 72h. We assessed the level of beta-2 adrenergic receptor (ADRB2) expression in these cells as well as global gene expression changes in NE treated Tcm cells by microarray analysis. Altered expressed genes after NE treatment were identified and further confirmed by RT-qPCR, and by ELISA for protein changes. We further determined whether the observed NE effects on memory CD8 T cells are mediated by ADRB2 using specific adrenergic receptor agonist and antagonists. Finally, we examined the levels of mRNA and protein of the NE-induced genes in healthy adults with high serum levels of NE (>150pg/mL) compared to low levels (<150pg/mL).ResultsWe found that memory (Tcm and Tem) CD8 T cells expressed a significantly higher level of ADRB2 compared to naïve cells. Consequently, memory CD8 T cells were significantly more sensitive than naïve cells to NE induced changes in gene expressions in vitro. Global gene expression analysis revealed that NE induced an elevated expression of inflammatory cytokines and chemokines in resting and activated memory CD8 T cells in addition to a reduced expression of growth-related cytokines. The effects of NE on memory CD8 T cells were primarily mediated by ADRB2 as confirmed by the adrenergic receptor agonist and antagonist assays. Finally, individuals with high serum levels of NE had similar elevated gene expressions observed in vitro compared to the low NE group.ConclusionsOur results demonstrate that NE preferentially modulates the functions of memory CD8 T cells by inducing inflammatory cytokine production and reducing activation-induced memory CD8 T cell expansion.

Dataset Information

Keratinocyte-Mediated Activation of the Cytokine TGF-? Maintains Skin Recirculating Memory CD8+ T Cells.

Publications

Keratinocyte-Mediated Activation of the Cytokine TGF-β Maintains Skin Recirculating Memory CD8<sup>+</sup> T Cells.

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