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Crit Care Med. 2017 Jan;45(1):e77-e85.

Suppression of T Cell Autophagy Results in Decreased Viability and Function of T Cells Through Accelerated Apoptosis in a Murine Sepsis Model.

Author information

1
1Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan. 2Department of Biomedical Science, Graduate School of Medicine, Chiba University, Chiba, Japan. 3Department of Reproductive Biology and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

Abstract

OBJECTIVE:

While type 1 programmed cell death (apoptosis) of T cells leads to immunosuppression in sepsis, a crosstalk between apoptosis and autophagy (type 2 programmed cell death) has not been shown. The aim of this study is to elucidate the details of the interaction between autophagy and immunosuppression.

DESIGN:

Laboratory investigation in the murine sepsis model.

SETTING:

University laboratory.

SUBJECTS:

Six- to 8-week-old male mice.

INTERVENTIONS:

We investigated the kinetics of autophagy in T cells from spleen in a cecal ligation and puncture model with green fluorescent protein-microtubule-associated protein light chain 3 transgenic mice. We analyzed apoptosis, mitochondrial homeostasis and cytokine production in T cells, and survival rate after cecal ligation and puncture using T cell-specific autophagy-deficient mice.

MEASUREMENTS AND MAIN RESULTS:

We observed an increase of autophagosomes, which was assessed by flow cytometry. However, an autophagy process in CD4 T cells during sepsis was insufficient including the accumulation of p62. On the other hand, a blockade of autophagy accelerated T cell apoptosis compared with the control mice, augmenting the gene expression of Bcl-2-like 11 and programmed cell death 1. Furthermore, mitochondrial accumulation in T cells occurred via a blockade of autophagy during sepsis. In addition, interleukin-10 production in CD4 T cells from the cecal ligation and puncture-operated knockout mice was markedly increased. Consequently, deficiency of autophagy in T cells significantly decreased the survival rate in the murine sepsis model.

CONCLUSIONS:

We demonstrated that blocking autophagy accelerated apoptosis and increased mortality in concordance with the insufficient autophagy process in CD4 T cells in the murine sepsis model, suggesting that T cell autophagy plays a protective role against apoptosis and immunosuppression in sepsis.

PMID:
27618275
PMCID:
PMC5364514
DOI:
10.1097/CCM.0000000000002016
[Indexed for MEDLINE]
Free PMC Article

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