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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 1

Generation and characterization of polyclonal memory T cells following infection.

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Generation and characterization of polyclonal memory T cells following i...
Naive B6 mice were infected with Listeria and allowed to develop a population of memory T cells. Mice were infected with LCMV 30 days later. Establishment of memory was assessed by flow cytometry 25 days after LCMV infection. (A) Schematic of experimental design. (B and C) Representative flow plots depicting CD44 expression on splenic CD4+ T cells following infection. (D) Expansion of CD44+ T cells in the spleen over time following antigenic challenge (n = 20/group). (E and F) Summary of frequency of CD44hi cells among CD4+ and CD8+ T cell compartments in memory mice on day 55 following infection (per schematic in A) in the blood, compared with the frequency of CD44hi cells in the blood of naive uninfected animals. Groups (n = 5) were compared with the Mann-Whitney nonparametric test. ****P < 0.0001. All data expressed as mean ± SEM.

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