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Chronic activation of the kinase IKK? impairs T cell function and survival.

ABSTRACT: Activation of the transcription factor NF-?B is critical for cytokine production and T cell survival after TCR engagement. The effects of persistent NF-?B activity on T cell function and survival are poorly understood. In this study, using a murine model that expresses a constitutively active form of inhibitor of NF-?B kinase ? (caIKK?) in a T cell-specific manner, we demonstrate that chronic inhibitor of NF-?B kinase ? signaling promotes T cell apoptosis, attenuates responsiveness to TCR-mediated stimulation in vitro, and impairs T cell responses to bacterial infection in vivo. caIKK? T cells showed increased Fas ligand expression and caspase-8 activation, and blocking Fas/Fas ligand interactions enhanced cell survival. T cell unresponsiveness was associated with defects in TCR proximal signaling and elevated levels of B lymphocyte-induced maturation protein 1, a transcriptional repressor that promotes T cell exhaustion. caIKK? T cells also showed a defect in IL-2 production, and addition of exogenous IL-2 enhanced their survival and proliferation. Conditional deletion of B lymphocyte-induced maturation protein 1 partially rescued the sensitivity of caIKK? T cells to TCR triggering. Furthermore, adoptively transferred caIKK? T cells showed diminished expansion and increased contraction in response to infection with Listeria monocytogenes expressing a cognate Ag. Despite their functional defects, caIKK? T cells readily produced proinflammatory cytokines, and mice developed autoimmunity. In contrast to NF-?B's critical role in T cell activation and survival, our study demonstrates that persistent IKK-NF-?B signaling is sufficient to impair both T cell function and survival.

SUBMITTER: Krishna S

PROVIDER: S-EPMC3401317 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Chronic activation of the kinase IKKβ impairs T cell function and survival.

Krishna Sruti S Xie Danli D Gorentla Balachandra B Shin Jinwook J Gao Jimin J Zhong Xiao-Ping XP

Journal of immunology (Baltimore, Md. : 1950) 20120629 3

Activation of the transcription factor NF-κB is critical for cytokine production and T cell survival after TCR engagement. The effects of persistent NF-κB activity on T cell function and survival are poorly understood. In this study, using a murine model that expresses a constitutively active form of inhibitor of NF-κB kinase β (caIKKβ) in a T cell-specific manner, we demonstrate that chronic inhibitor of NF-κB kinase β signaling promotes T cell apoptosis, attenuates responsiveness to TCR-mediat ...[more]

PMID: 22753932

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Project description:Does medroxyprogesterone acetate (MPA) impair human dendritic cell (DC) activation and function?In 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).MPA 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.This cross-sectional study examined MPA-mediated effects on the activation and function of human primary untouched peripheral blood DCs.Human 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.Several 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.While 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.Identification 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.Funding provided by the NIH (grant R01HD072663) and The Ohio State University College of Medicine. The authors have no con?icts of interest to declare.

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Chronic activation of the kinase IKK? impairs T cell function and survival.

Publications

Chronic activation of the kinase IKKβ impairs T cell function and survival.

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