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Increased attrition of memory T cells during sepsis requires 2B4
Jianfeng Xie, … , Craig M. Coopersmith, Mandy L. Ford
Jianfeng Xie, … , Craig M. Coopersmith, Mandy L. Ford
Published May 2, 2019
Citation Information: JCI Insight. 2019;4(9):e126030. https://doi.org/10.1172/jci.insight.126030.
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Research Article Immunology Infectious disease

Increased attrition of memory T cells during sepsis requires 2B4

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Abstract

Recent seminal studies have revealed that laboratory mice differ from adult humans with regard to the frequency, number, and distribution of memory T cells. Because our data show that memory T cells are more susceptible to sepsis-induced death than naive T cells, in this study we developed a model in which mice possess a memory T cell compartment more similar to that of adult humans, to better study immune responses during sepsis in the more physiologically relevant context of high frequencies of memory T cells. Using this model, we found that CD44hi memory T cells significantly upregulated the coinhibitory molecule 2B4 during sepsis, and 2B4+ memory T cells coexpressed markers of both activation and exhaustion. Genetic deficiency in 2B4 resulted in decreased mortality during sepsis. Mechanistically, this decreased mortality was associated with reduced caspase-3/7+ apoptotic T cells in 2B4–/– relative to WT, septic hosts. These results were corroborated by analysis of PBMCs isolated from human patients with sepsis, which showed increased frequencies of caspase-3/7+ apoptotic cells among 2B4+ relative to 2B4– T cells. Thus, 2B4 plays a critical role in sepsis-induced apoptosis in both murine memory T cells and those isolated from human patients with sepsis.

Authors

Jianfeng Xie, Ching-wen Chen, Yini Sun, Sonia J. Laurie, Wenxiao Zhang, Shunsuke Otani, Gregory S. Martin, Craig M. Coopersmith, Mandy L. Ford

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Figure 5

2B4+CD8+ T cells in patients with sepsis exhibited increased cell apoptosis.

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2B4+CD8+ T cells in patients with sepsis exhibited increased cell apopto...
PBMCs were isolated from n = 14 patients with sepsis under an IRB-approved protocol within 24 hours of a sepsis diagnosis and from n = 10 normal healthy controls. (A) Frequencies of memory T cell subsets in n = 10 HDs versus n = 7 patients with sepsis. Naive T cells (Tnaive) were identified by gating on CD45RA+CCR7+; central memory T cells (Tcm) were gated on CD45RA–CCR7+; Tem were gated on CD45RA–CCR7–; and Temra were gated on CD45RA+CCR7–. Cells from septic patients 1–7 as identified in Supplemental Table 1 were used in A. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. (B) Active caspase 3/7 staining on CD4+ and CD8+ T cell subsets isolated from n = 7 patients with sepsis was determined by flow cytometry. Summary data of frequencies of active caspase-3/7+ T cells within memory T cell subsets of CD4+ T cells (left) and CD8+ T cells (right) are displayed. (C) CD8+ T cells were further divided into 2B4– and 2B4+ populations and caspase-3/7 activity was assessed. Representative flow plots for caspase-3/7 staining in CD8+2B4– and CD8+2B4+ T cells. Summary data of frequencies of caspase-3/7+ cells within 2B4–CD8+ and 2B4+CD8+ T cells. Cells from septic patients 8–14 as identified in Supplemental Table 1 were used in B and C. *P < 0.05. SSC, side scatter.

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