Inefficient Recovery of Repeatedly Stimulated Memory CD8 T Cells after Polymicrobial Sepsis Induction Leads to Changes in Memory CD8 T Cell Pool Composition

Steven J. Moioffer, Roger R. Berton, Patrick W. McGonagill, Isaac J. Jensen, Thomas S. Griffith, Vladimir P. Badovinac

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Long-lasting sepsis-induced immunoparalysis has been principally studied in primary (1) memory CD8 T cells; however, the impact of sepsis on memory CD8 T cells with a history of repeated cognate Ag encounters is largely unknown but important in understanding the role of sepsis in shaping the pre-existing memory CD8 T cell compartment. Higher-order memory CD8 T cells are crucial in providing immunity against common pathogens that reinfect the host or are generated by repeated vaccination. In this study, we analyzed peripheral blood from septic patients and show that memory CD8 T cells with defined Ag specificity for recurring CMV infection proliferate less than bulk populations of central memory CD8 T cells. Using TCR-transgenic T cells to generate 1 and higher-order (quaternary [4]) memory T cells within the same host, we demonstrate that the susceptibility and loss of both memory subsets are similar after sepsis induction, and sepsis diminished Ag-dependent and -independent (bystander) functions of these memory subsets equally. Both the 1 and 4 memory T cell populations proliferated in a sepsis-induced lymphopenic environment; however, due to the intrinsic differences in baseline proliferative capacity, expression of receptors (e.g., CD127/CD122), and responsiveness to homeostatic cytokines, 1 memory T cells become overrepresented over time in sepsis survivors. Finally, IL-7/anti-IL-7 mAb complex treatment early after sepsis induction preferentially rescued the proliferation and accumulation of 1 memory T cells, whereas recovery of 4 memory T cells was less pronounced. Thus, inefficient recovery of repeatedly stimulated memory cells after polymicrobial sepsis induction leads to changes in memory T cell pool composition, a notion with important implications in devising strategies to recover the number and function of pre-existing memory CD8 T cells in sepsis survivors.

Original languageEnglish (US)
Pages (from-to)168-179
Number of pages12
JournalJournal of Immunology
Volume210
Issue number2
DOIs
StatePublished - Jan 15 2023

Bibliographical note

Funding Information:
This work was supported by National Institute of General Medical Sciences Grant GM134880 and National Institute of Allergy and Infectious Diseases Grant AI114543 (to V.P.B.), National Institute of General Medical Sciences Grant GM140881 (to T.S.G.), National Institute of Allergy and Infectious Diseases Grant AI007485 (to R.R.B. and I.J.J.), the Holden Comprehensive Cancer Center at the University of Iowa and its National Cancer Institute Award CA086862 (to V.P.B.), and by U.S. Department of Veterans Affairs Merit Review Award I01BX001324 (to T.S.G.). T.S.G. is the recipient of U.S. Department of Veterans Affairs Research Career Scientist Award IK6BX006192. V.P.B. is a University of Iowa Distinguished Scholar. We thank members of our laboratories for technical assistance and helpful discussions.

Funding Information:
This work was supported by National Institute of General Medical Sciences Grant GM134880 and National Institute of Allergy and Infectious Diseases Grant AI114543 (to V.P.B.), National Institute of General Medical Sciences Grant GM140881 (to T.S.G.), National Institute of Allergy and Infectious Diseases Grant AI007485 (to R.R.B. and I.J.J.), the Holden Comprehensive Cancer Center at the University of Iowa and its National

Funding Information:
Cancer Institute Award CA086862 (to V.P.B.), and by U.S. Department of Veterans Affairs Merit Review Award I01BX001324 (to T.S.G.). T.S.G. is the recipient of U.S. Department of Veterans Affairs Research Career Scientist Award IK6BX006192. V.P.B. is a University of Iowa Distinguished Scholar.

Publisher Copyright:
Copyright © 2023 by The American Association of Immunologists, Inc.

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