title: Interferon regulatory factor 4 sustains CD8(+) T cell expansion and effector differentiation.
abstract: Upon infection, CD8(+) T cells 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(+) T cell activation, was vital for sustaining the expansion and effector differentiation of CD8(+) T cells. Mechanistically, IRF4 promoted the expression and function of Blimp1 and T-bet, two transcription factors required for CD8(+) T cell effector differentiation, and simultaneously repressed genes that mediate cell cycle arrest and apoptosis. Selective ablation of Irf4 in peripheral CD8(+) T cells impaired antiviral CD8(+) T cell responses, viral clearance, and CD8(+) T cell-mediated host recovery from influenza infection. IRF4 expression was regulated by T cell 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(+) T cell responses.
authors.affiliation: Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Microbiology and Immunology, Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Shuyu
authors.initials: S
authors.lastname: Yao
authors.forename: Bruno Fernando
authors.initials: BF
authors.lastname: Buzo
authors.forename: Duy
authors.initials: D
authors.lastname: Pham
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Taparowsky
authors.forename: Mark H
authors.initials: MH
authors.lastname: Kaplan
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D002478:Cells, Cultured / Q000166:cytology; D018920:Coculture Techniques; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000037:antagonists & inhibitors; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000276:immunology / Q000821:virology; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013047:Specific Pathogen-Free Organisms; D020825:T-Box Domain Proteins / Q000096:biosynthesis / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D010948:Viral Plaque Assay; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050835:Interferon Regulatory Factors; D008565:Membrane Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011518:Proto-Oncogene Proteins; D011948:Receptors, Antigen, T-Cell; D020825:T-Box Domain Proteins; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4; C000606776:Bcl2l11 protein, mouse; C513258:Prdm1 protein, mouse; C546843:mTOR protein, mouse