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Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

ABSTRACT: Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescues the acetate-induced inhibition of T cell migration, primary mouse cortactin knockout T cells exhibited impaired migration. Acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.

SUBMITTER: Azizov V

PROVIDER: S-EPMC10362326 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

Azizov Vugar V Hübner Michel M Frech Michael M Hofmann Jörg J Kubankova Marketa M Lapuente Dennis D Tenbusch Matthias M Guck Jochen J Schett Georg G Zaiss Mario M MM

iScience 20230628 7

Alcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart, and brain. Alcohol also has strong immunoregulatory properties. Here, we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acet ...[more]

PMID: 37485352

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Project description:Study questionDoes medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?Summary answerIn vitro MPA treatment suppressed expression of CD40 and CD80 by human primary DCs responding to Toll-like receptor 3 (TLR3) agonist stimulation (i.e. DC activation). Moreover, this MPA-mediated decrease in CD40 expression impaired DC capacity to stimulate T cell proliferation (i.e. DC function).What is known alreadyMPA is the active molecule in Depo-Provera(®) (DMPA), a commonly used injectable hormonal contraceptive (HC). Although DMPA treatment of mice prior to viral mucosal tissue infection impaired the capacity of DCs to up-regulate CD40 and CD80 and prime virus-specific T cell proliferation, neither DC activation marker expression nor the ability of DCs to promote T cell proliferation were affected by in vitro progesterone treatment of human DCs generated from peripheral blood monocytes.Study design, size, durationThis cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.Participants/materials, setting, methodsHuman DCs isolated from peripheral blood mononuclear cells by negative immunomagnetic selection were incubated for 24 h with various concentrations of MPA. After an additional 24 h incubation with the TLR3 agonist polyinosinic:polycytidylic acid (poly I:C), flow cytometry was used to evaluate DC phenotype (i.e. expression of CD40, CD80, CD86, and HLA-DR). In separate experiments, primary untouched human DCs were sequentially MPA-treated, poly I:C-activated, and incubated for 7 days with fluorescently labeled naïve allogeneic T cells. Flow cytometry was then used to quantify allogeneic T cell proliferation.Main results and the role of chanceSeveral pharmacologically relevant concentrations of MPA dramatically reduced CD40 and CD80 expression in human primary DCs responding to the immunostimulant poly I:C. In addition, MPA-treated DCs displayed a reduced capacity to promote allogeneic CD4(+) and CD8(+) T cell proliferation. In other DC: T cell co-cultures, the addition of antibody blocking the CD40-CD154 (CD40L) interaction mirrored the decreased T cell proliferation produced by MPA treatment, while addition of recombinant soluble CD154 restored the capacity of MPA-treated DCs to induce T cell proliferation to levels produced by non-MPA-treated controls.Limitations, reason for cautionWhile our results newly reveal that pharmacologically relevant MPA concentrations suppress human DC function in vitro, additional research is needed to learn if DMPA similarly inhibits DC maturation and function in the human female genital tract.Wider implications of the findingsIdentification of a mechanism by which MPA impairs human DC activation and function increases the biological plausibility for the relationships currently suspected between DMPA use and enhanced susceptibility to genital tract infection.Study funding/competing interestsFunding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no conﬂicts of interest to declare.

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Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

Publications

Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation.

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