Requirement for T-bet in the aberrant differentiation of unhelped memory CD8+ T cells.
Immunity to intracellular pathogens requires dynamic balance between terminal differentiation of short-lived, cytotoxic effector CD8+ T cells and self-renewal of central-memory CD8+ T cells. We now show that T-bet represses transcription of IL-7Ralpha and drives differentiation of effector and effector-memory CD8+ T cells at the expense of central-memory cells. We also found T-bet to be overexpressed in CD8+ T cells that differentiated in the absence of CD4+ T cell help, a condition that is associated with defective central-memory formation. Finally, deletion of T-bet corrected the abnormal phenotypic and functional properties of "unhelped" memory CD8+ T cells. T-bet, thus, appears to function as a molecular switch between central- and effector-memory cell differentiation. Antagonism of T-bet may, therefore, represent a novel strategy to offset dysfunctional programming of memory CD8+ T cells.
Intlekofer
Andrew M
AM
Abramson Family Cancer Research Institute, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Takemoto
Naofumi
N
Kao
Charlly
C
Banerjee
Arnob
A
Schambach
Felix
F
Northrop
John K
JK
Shen
Hao
H
Wherry
E John
EJ
Reiner
Steven L
SL
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation; D007156:Immunologic Memory / Q000276:immunology*; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D051379:Mice; D012097:Repressor Proteins / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098815:T-bet Transcription Factor
D053699:Interleukin-7 Receptor alpha Subunit; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
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