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

Frances V. Sjaastad, Tamara A. Kucaba, Thamotharampillai Dileepan, Whitney Swanson, Cody Dail, Javier Cabrera-Perez, Katherine A. Murphy, Vladimir P. Badovinac, Thomas S. Griffith

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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-Ab-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 OVA323-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.

Original languageEnglish (US)
Article number1786
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Aug 12 2020

Bibliographical note

Funding Information:
Funding. This work was supported by National Institutes of Health grants R01GM115462 (TG), R01AIGM113961 (VB), R35GM134880 (VB), T32CA009138 (FS), T32AI007313 (FS and JC-P), T35AI118620 (CD), and a Veterans Administration Merit Review Award (I01BX001324; TG). This work was also supported in part by NIH P30 CA77598 utilizing the Masonic Cancer Center, University of Minnesota Flow Cytometry shared resource.

Publisher Copyright:
© Copyright © 2020 Sjaastad, Kucaba, Dileepan, Swanson, Dail, Cabrera-Perez, Murphy, Badovinac and Griffith.

Keywords

  • CD4 T cells
  • IFN-gamma
  • immune suppression
  • memory
  • sepsis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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