TY - JOUR
T1 - Interferon regulatory factor 4 sustains CD8+ T cell expansion and effector differentiation
AU - Yao, Shuyu
AU - Buzo, Bruno Fernando
AU - Pham, Duy
AU - Jiang, Li
AU - Taparowsky, Elizabeth J.
AU - Kaplan, Mark H.
AU - Sun, Jie
N1 - Funding Information:
We thank M. Hufford for critical reading of the manuscript. We thank National Institutes of Health tetramer facility and D. Hildeman for reagents. This work was supported by the US National Institutes of Health grants (T32 HL007910 to D.P., AI099753 to J.S., AI045515 to M.H.K., and CA114381 to E.J.T.) and Showalter trust funds (to J.S.).
PY - 2013/11/14
Y1 - 2013/11/14
N2 - Upon infection, CD8+ Tcells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8+ Tcell activation, was vital for sustaining the expansion and effector differentiation of CD8+ Tcells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8+ Tcell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8+ Tcells impaired antiviral CD8+ Tcell responses, viral clearance, and CD8+ Tcell-mediated host recovery from influenza infection. IRF4 expression was regulated by Tcell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8+ Tcell responses.
AB - Upon infection, CD8+ Tcells undergo a stepwise process of early activation, expansion, and differentiation into effector cells. How these phases are transcriptionally regulated is incompletely defined. Here, we report that interferon regulatory factor 4 (IRF4), dispensable for early CD8+ Tcell activation, was vital for sustaining the expansion and effector differentiation of CD8+ Tcells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8+ Tcell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8+ Tcells impaired antiviral CD8+ Tcell responses, viral clearance, and CD8+ Tcell-mediated host recovery from influenza infection. IRF4 expression was regulated by Tcell receptor (TCR) signaling strength via mammalian target of rapamycin (mTOR). Our data reveal that IRF4 translates differential strength of TCR signaling into different quantitative and qualitative CD8+ Tcell responses.
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U2 - 10.1016/j.immuni.2013.10.007
DO - 10.1016/j.immuni.2013.10.007
M3 - Article
C2 - 24211184
AN - SCOPUS:84887507709
SN - 1074-7613
VL - 39
SP - 833
EP - 845
JO - Immunity
JF - Immunity
IS - 5
ER -