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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 3

2B4 coinhibitory receptor is preferentially upregulated on CD44hi memory T cells during sepsis.

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2B4 coinhibitory receptor is preferentially upregulated on CD44hi memory...
Naive B6 mice were infected with Listeria. Mice were infected with LCMV 30 days later. CLP was performed 25 days after LCMV infection, and expression of 2B4 on CD44lo and CD44hi CD4+ and CD8+ T cells in the spleen was assessed via flow cytometry. (A) Frequency of 2B4 expression on total CD4+ T cells. (B) Summary data depicting frequency of 2B4 expression on CD44loCD4+ and CD44hiCD4+ T cells. (C) Frequency of 2B4 expression on total CD8+ T cells. (D) Summary data depicting frequency of 2B4 expression on CD44lo and CD44hi CD8+ T cells. (E) Representative plots depicting frequency of CD25, CD69, and PD-1 within 2B4+CD4+ and 2B4–CD4+ T cell compartments. (F) Summary of data presented in E. Percentages of CD25+, CD69+, and PD-1+ of 2B4– cells were calculated by dividing Q1 in the plot shown by Q4. Percentages of CD25+, CD69+, and PD-1+ of 2B4+ cells were calculated by dividing Q2 in the plot shown by Q3. (G) Representative plots depicting frequency of CD25, CD69, and PD-1 within 2B4+CD4+ and 2B4–CD8+ T cell compartments. (H) Summary of data presented in G. Percentages of CD25+, CD69+, and PD-1+ of 2B4– cells were calculated by dividing Q1 in the plot shown by Q4. Percentages of CD25+, CD69+, and PD-1+ of 2B4+ cells were calculated by dividing Q2 in the plot shown by Q3. Groups (n = 10) were compared with the Mann-Whitney nonparametric test. *P < 0.05, ***P < 0.001, and ****P < 0.0001.

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