Anomalous type 17 response to viral infection by CD8+ T cells lacking T-bet and eomesodermin.
When intracellular pathogens invade mammalian hosts, naïve CD8+ T cells differentiate into cytotoxic killers, which lyse infected target cells and secrete cytokines that activate intracellular microbicides. We show that CD8+ T cells deficient in the transcription factors T-bet and eomesodermin (Eomes) fail to differentiate into functional killers required for defense against lymphocytic choriomeningitis virus. Instead, virus-specific CD8+ T cells lacking both T-bet and Eomes differentiate into an interleukin-17-secreting lineage, reminiscent of the helper T cell fate that has been implicated in autoimmunity and extracellular microbial defense. Upon viral infection, mice with T cells lacking both T-bet and Eomes develop a CD8+ T cell-dependent, progressive inflammatory and wasting syndrome characterized by multi-organ infiltration of neutrophils. T-bet and Eomes, thus, ensure that CD8+ T cells adopt an appropriate course of intracellular rather than extracellular destruction.
Intlekofer
Andrew M
AM
Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
Banerjee
Arnob
A
Takemoto
Naofumi
N
Gordon
Scott M
SM
Dejong
Caitlin S
CS
Shin
Haina
H
Hunter
Christopher A
CA
Wherry
E John
EJ
Lindsten
Tullia
T
Reiner
Steven L
SL
D000818:Animals; D000956:Antigens, Viral / Q000276:immunology; D001117:Arenaviridae Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008212:Lymphocyte Depletion; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000302:isolation & purification / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication; D019282:Wasting Syndrome / Q000276:immunology / Q000473:pathology / Q000821:virology; D000098815:T-bet Transcription Factor
D000956:Antigens, Viral; C491198:Eomes protein, mouse; D020381:Interleukin-17; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma