Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells
- University of Iowa, United States
- George Washington University, United States
- Hackensack University Medical Center, United States
- University of Minnesota, United States
Abstract
The global health burden due to sepsis and the associated cytokine storm is substantial. While early intervention has improved survival during the cytokine storm, those that survive can enter a state of chronic immunoparalysis defined by transient lymphopenia and functional deficits of surviving cells. Memory CD8 T cells provide rapid cytolysis and cytokine production following re-encounter with their cognate antigen to promote long-term immunity, and CD8 T cell impairment due to sepsis can pre-dispose individuals to re-infection. While the acute influence of sepsis on memory CD8 T cells has been characterized, if and to what extent pre-existing memory CD8 T cells recover remains unknown. Here, we observed that central memory CD8 T cells (TCM) from septic patients proliferate more than those from healthy individuals. Utilizing LCMV immune mice and a CLP model to induce sepsis, we demonstrated that TCM proliferation is associated with numerical recovery of pathogen-specific memory CD8 T cells following sepsis-induced lymphopenia. This increased proliferation leads to changes in composition of memory CD8 T cell compartment and altered tissue localization. Further, memory CD8 T cells from sepsis survivors have an altered transcriptional profile and chromatin accessibility indicating long-lasting T cell intrinsic changes. The sepsis-induced changes in the composition of the memory CD8 T cell pool and transcriptional landscape culminated in altered T cell function and reduced capacity to control L. monocytogenes infection. Thus, sepsis leads to long-term alterations in memory CD8 T cell phenotype, protective function and localization potentially changing host capacity to respond to re-infection.
Data availability
Sequencing data are deposited in GEO under accession code GSE174358source data for all figures are provided in associated excel files.
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Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells (RNA-Seq)NCBI Gene Expression Omnibus, GSE174358.
Article and author information
Author details
Vladimir P Badovinac
Funding
National Institutes of Health (R01AI114543)
- Vladimir P Badovinac
National Institutes of Health (R21AI157121)
- Jon CD Houtman
National Institutes of Health (T32AI007511)
- Isaac J jensen
National Institutes of Health (T32AI007485)
- Isaac J jensen
Veterans Health Administration (I0BX001324)
- Thomas S Griffith
National Cancer Institute (P30CA086862)
- Jon CD Houtman
National Institutes of Health (R21AI147064)
- Vladimir P Badovinac
National Institutes of Health (R21AI151183)
- Vladimir P Badovinac
National Institutes of Health (R01GM115462)
- Thomas S Griffith
National Institutes of Health (R35GM134880)
- Vladimir P Badovinac
National Institutes of Health (R35GM140881)
- Thomas S Griffith
National Institutes of Health (R01AI112579)
- Hai-Hui Xue
National Institutes of Health (R01AI121080)
- Hai-Hui Xue
- Weiqun Peng
National Institutes of Health (R01AI139874)
- Hai-Hui Xue
- Weiqun Peng
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Experimental procedures using mice were approved by University of Iowa Animal Care and Use Committee under ACURF protocol #6121915 and #9101915. The experiments performed followed Office of Laboratory Animal Welfare guidelines and PHS Policy on Humane Care and Use of Laboratory Animals. Cervical dislocation was used as the euthanasia method of all experimental mice. Inbred C57Bl/6 (B6, Thy1.2) and TCR-transgenic (TCR-Tg) P14 (Thy1.1) mice were purchased from the National Cancer Institute (Frederick, MD) and maintained in the animal facilities at the University of Iowa at the appropriate biosafety level according to the University of Iowa Animal Care and Use Committee and National Institutes of Health guidelines. Male and female mice >6 weeks of age were used for experiments; no discernable differences were observed based on sex of the animals.
Human subjects: Patients were recruited at the University of Iowa Hospitals and Clinics, an 811-bed academic tertiary care center. Blood sample acquisition, patient data collection, and analysis were approved by the University of Iowa Institutional Review Board (ID #201804822). Informed consent was obtained from patients or their legally authorized representatives.
Copyright
© 2021, jensen et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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