Bystander chronic infection negatively impacts development of CD8(+) T cell memory.
Epidemiological evidence suggests that chronic infections impair immune responses to unrelated pathogens and vaccines. The underlying mechanisms, however, are unclear and distinguishing effects on priming versus development of immunological memory has been challenging. We investigated whether bystander chronic infections impact differentiation of memory CD8(+) T cells, the hallmark of protective immunity against intracellular pathogens. Chronic bystander infections impaired development of memory CD8(+) T cells in several mouse models and humans. These effects were independent of initial priming and were associated with chronic inflammatory signatures. Chronic inflammation negatively impacted the number of bystander CD8(+) T cells and their memory development. Distinct underlying mechanisms of altered survival and differentiation were revealed with the latter regulated by the transcription factors T-bet and Blimp-1. Thus, exposure to prolonged bystander inflammation impairs the effector to memory transition. These data have relevance for immunity and vaccination during persisting infections and chronic inflammation.
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Erietta
E
Stelekati
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Haina
H
Shin
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Travis A
TA
Doering
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Douglas V
DV
Dolfi
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Carly G
CG
Ziegler
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Daniel P
DP
Beiting
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Lucas
L
Dawson
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Jennifer
J
Liboon
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
David
D
Wolski
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Mohammed-Alkhatim A
MA
Ali
Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Peter D
PD
Katsikis
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA.
Hao
H
Shen
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
David S
DS
Roos
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Division of Hematology/Oncology, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
W Nicholas
WN
Haining
Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Georg M
GM
Lauer
Department of Microbiology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA; Institute for Immunology, University of Pennsylvania Perelman School Medicine, Philadelphia, PA 19104, USA. Electronic address: wherry@mail.med.upenn.edu.
E John
EJ
Wherry
D019264:Adoptive Transfer; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D024201:Bystander Effect / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D002908:Chronic Disease; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000074462:Positive Regulatory Domain I-Binding Factor 1; D020825:T-Box Domain Proteins / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D014777:Virus Diseases / Q000276:immunology*; D000098815:T-bet Transcription Factor
C513258:Prdm1 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1