Increased attrition of memory T cells during sepsis requires 2B4

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

doi:10.1172/jci.insight.126030

Cited by 15 publications

(20 citation statements)

References 46 publications

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“…The number of tissue-resident memory CD8 T cells is maintained after sepsis, as well as their ability to produce effector cytokine after re-stimulation. In contrast to the aforementioned similar attrition of naïve and memory CD8 T cells after sepsis, it was recently suggested by Xie et al that CD44 hi CD8 T cells in “memory mice” (generated via Listeria and LCMV infection) exhibited significant attrition after CLP while this was not the case for naïve CD44 lo CD8 T cells ( 73 ). It was surprising to see that CLP sepsis did not lead to a reduction in CD44 lo CD8 T cells, as such a reduction has been noted in other papers ( 14 , 39 , 40 , 74 – 77 ).…”

Section: Discussionmentioning

confidence: 87%

Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity

et al. 2020

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Patients who survive sepsis display prolonged immune dysfunction and heightened risk of secondary infection. CD4 T cells support a variety of cells required for protective immunity, and perturbations to the CD4 T cell compartment can decrease overall immune system fitness. Using the cecal ligation and puncture (CLP) mouse model of sepsis, we investigated the impact of sepsis on endogenous Ag-specific memory CD4 T cells generated in C57BL/6 (B6) mice infected with attenuated Listeria monocytogenes (Lm) expressing the I-A b -restricted 2W1S epitope (Lm-2W). The number of 2W1S-specific memory CD4 T cells was significantly reduced on day 2 after sepsis induction, but recovered by day 14. In contrast to the transient numerical change, the 2W1S-specific memory CD4 T cells displayed prolonged functional impairment after sepsis, evidenced by a reduced recall response (proliferation and effector cytokine production) after restimulation with cognate Ag. To define the extent to which the observed functional impairments in the memory CD4 T cells impacts protection to secondary infection, B6 mice were infected with attenuated Salmonella enterica- 2W ( Se -2W) 30 days before sham or CLP surgery, and then challenged with virulent Se- 2W after surgery. Pathogen burden was significantly higher in the CLP-treated mice compared to shams. Similar reductions in functional capacity and protection were noted for the endogenous OVA 323 -specific memory CD4 T cell population in sepsis survivors upon Lm-OVA challenge. Our data collectively show CLP-induced sepsis alters the number and function of Ag-specific memory CD4 T cells, which contributes (in part) to the characteristic long-lasting immunoparalysis seen after sepsis.

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Section: Discussionmentioning

confidence: 87%

Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity

et al. 2020

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“…While this model may mimic bacterial challenge following specific viral or bacterial infection, the T cell clonal memory developed in response to Listeria and LCMV are very specific with well-defined, finite epitope specificity. The anti-CD3 model activates a far more diverse repertoire of T cell clones, likely causing variation in the response to CLP (23).…”

Section: Discussionmentioning

confidence: 99%

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

et al. 2020

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The role of T cell memory in sepsis is poorly understood. Recent work has demonstrated that mice exposed to frequent antigenic stimulation, in contrast to laboratory mice, better recapitulate the human T cell repertoire. This difference may profoundly alter responses to inflammatory insults. We induced isolated T cell memory by inoculating C57Bl/6 mice with an anti-CD3ϵ activating antibody, a process we term “immune education.” These mice were subjected to the cecal ligation and puncture (CLP) model of sepsis and responses were compared to those of isotype-treated controls. CLP-induced increases in 1) CD4 T cell production and serum levels of IFNγ, 2) CD8 T cell granzyme B levels, and 3) innate cell function were all more pronounced in educated mice than in control mice. Immune education increased CLP-induced liver injury and decreased survival. The differences in responses to CLP were not recapitulated in mice with either isolated CD4 or isolated CD8 T cell memory. Relative to controls, CLP in educated CD8−/− mice (isolated CD4 memory) increased monocyte-derived dendritic cells. Combined CD4 and CD8 memory did not increase monocyte-derived dendritic cells; this combination recapitulated increases in neutrophil and inflammatory monocyte numbers in educated wild-type mice. Induction of T cell memory prior to CLP alters immune responses, organ function, and survival. Both CD4 and CD8 memory T cells play important and independent roles in this response. These findings have profound implications for the development of murine models of human inflammatory disorders such as infection and sepsis.

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“…Another limitation of this study was the use of immunologically naive mice, which have a lower frequency of memory T cells than do humans. We have previously published data indicating that mice sequentially infected with viral and bacterial infections have a memory compartment that better reflects what is observed in humans ( Xie et al., 2019a ). Although we failed to observe an association between IL-27 signaling and PD-1 expression in previously healthy septic mice, the findings in mice with pre-existing cancer may be different because there is an association between IL-27 signaling and PD-1 expression in the setting of cancer.…”

Section: Discussionmentioning

confidence: 96%

“…Naive and memory CD4 + T cell numbers are significantly reduced following CLP. Although the number of naive CD8 + T cells is similar between CLP and sham-surgery mice at all time points, the number of memory CD8 + T cells is reduced following sepsis ( Serbanescu et al., 2016 ; Xie et al., 2019a ). One day after CLP surgery, the number of memory CD8 + T cells is reduced by 44% and remains reduced for three days after surgery ( Serbanescu et al., 2016 ).…”

Section: Introductionmentioning

confidence: 92%

“…One day after CLP surgery, the number of memory CD8 + T cells is reduced by 44% and remains reduced for three days after surgery ( Serbanescu et al., 2016 ). Co-inhibitory markers such as TIGIT and PD-1 are also highly upregulated on T cells and linked to their apoptosis during sepsis ( Boomer et al., 2012 ; Chen et al., 2017 ; Sjaastad et al., 2018 ; Ammer-Herrmenau et al., 2019 ; Xie et al., 2019a , 2019b ).…”

Section: Introductionmentioning

confidence: 99%

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The IL-27 receptor regulates TIGIT on memory CD4+ T cells during sepsis

et al. 2021

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Summary Sepsis is a leading cause of morbidity and mortality associated with significant impairment in memory T cells. These changes include the upregulation of co-inhibitory markers, a decrease in functionality, and an increase in apoptosis. Due to recent studies describing IL-27 regulation of TIGIT and PD-1, we assessed whether IL-27 impacts these co-inhibitory molecules in sepsis. Based on these data, we hypothesized that IL-27 was responsible for T cell dysfunction during sepsis. Using the cecal ligation and puncture (CLP) sepsis model, we found that IL-27Rα was associated with the upregulation of TIGIT on memory CD4 + T cells following CLP. However, IL-27 was not associated with sepsis mortality.

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Increased attrition of memory T cells during sepsis requires 2B4

Cited by 15 publications

References 46 publications

Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity

Polymicrobial Sepsis Impairs Antigen-Specific Memory CD4 T Cell-Mediated Immunity

CD4 and CD8 T Cell Memory Interactions Alter Innate Immunity and Organ Injury in the CLP Sepsis Model

The IL-27 receptor regulates TIGIT on memory CD4+ T cells during sepsis

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