Severity of sepsis determines the degree of impairment observed in circulatory and tissue-resident memory cd8 t cell populations

Steven J. Moioffer, Derek B. Danahy, Stephanie van de Wall, Isaac J. Jensen, Frances V. Sjaastad, Scott M. Anthony, John T. Harty, Thomas S. Griffith, Vladimir P. Badovinac

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Sepsis reduces the number and function of memory CD8 T cells within the host, contributing to the long-lasting state of immunoparalysis. Interestingly, the relative susceptibility of memory CD8 T cell subsets to quantitative/qualitative changes differ after cecal ligation and puncture (CLP)-induced sepsis. Compared with circulatory memory CD8 T cells (TCIRCM), moderate sepsis (0-10% mortality) does not result in numerical decline of CD8 tissue-resident memory T cells (TRM),which retain their "sensing and alarm"IFN-γ-mediated effector function. To interrogate this biologically important dichotomy, vaccinia virus-immune C57BL/6 (B6) mice containing CD8 TCIRCM and skin TRM underwent moderate or severe (∼50% mortality) sepsis. Severe sepsis led to increased morbidity and mortality characterized by increased inflammation compared with moderate CLP or sham controls. Severe CLP mice also displayed increased vascular permeability in the ears. Interestingly, skin CD103+ CD8 TRM, detected by i.v. exclusion or two-photon microscopy, underwent apoptosis and subsequent numerical loss following severe sepsis, which was not observed in mice that experienced moderate CLP or sham surgeries. Consequently, severe septic mice showed diminished CD8 T cell-mediated protection to localized skin reinfection. Finally, the relationship between severity of sepsis and demise in circulatory versus tissue-embedded memory CD8 T cell populations was confirmed by examining tumor-infiltrating and nonspecific CD8 T cells in B16 melanoma tumors. Thus, sepsis can differentially affect the presence and function of Ag-specific CD8 T cells that reside inside tissues/tumors depending on the severity of the insult, a notion with direct relevance to sepsis survivors and their ability to mount protective memory CD8 T cell-dependent responses to localized Ag re-encounter.

Original languageEnglish (US)
Pages (from-to)1871-1881
Number of pages11
JournalJournal of Immunology
Issue number7
StatePublished - Oct 1 2021

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health (NIH) Grants GM134880 (to V.P.B.), AI114543 and AI151183 (to V.P.B. and J.T.H.), GM115462 (to T.S.G.), R35GM140881 (to T.S.G.), T32AI007485 (to D.B.D. and I.J.J.), and AI42767, AI085515, and AI100527, (to J.T.H.). Support was also received from Foundation for the NIH T325T32HL007 (to S.M.A.) and the Holden Comprehensive Cancer Center at The University of Iowa and its National Cancer Institute Award P30CA086862 (to V.P.B.). This work was also supported by Veterans Administration Merit Review Award I01BX001324 (to T.S.G.).

Publisher Copyright:
© 2021 by TheAmericanAssociation of Immunologists, Inc.


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