title: IRF4 Regulates the Ratio of T-Bet to Eomesodermin in CD8+ T Cells Responding to Persistent LCMV Infection.
abstract: CD8+ T cell exhaustion commonly occurs in chronic infections and cancers. During T cell exhaustion there is a progressive and hierarchical loss of effector cytokine production, up-regulation of inhibitory co-stimulatory molecules, and eventual deletion of antigen specific cells by apoptosis. A key factor that regulates T cell exhaustion is persistent TCR stimulation. Loss of this interaction results in restoration of CD8+ T cell effector functions in previously exhausted CD8+ T cells. TCR stimulation is also important for the differentiation of Eomeshi anti-viral CD8+ effector T cells from T-bethi precursors, both of which are required for optimal viral control. However, the molecular mechanisms regulating the differentiation of these two cell subsets and the relative ratios required for viral clearance have not been described. We show that TCR signal strength regulates the relative expression of T-bet and Eomes in antigen-specific CD8+ T cells by modulating levels of IRF4. Reduced IRF4 expression results in skewing of this ratio in the favor of Eomes, leading to lower proportions and numbers of T-bet+ Eomes- precursors and poor control of LCMV-clone 13 infection. Manipulation of this ratio in the favor of T-bet restores the differentiation of T-bet+ Eomes- precursors and the protective balance of T-bet to Eomes required for efficient viral control. These data highlight a critical role for IRF4 in regulating protective anti-viral CD8+ T cell responses by ensuring a balanced ratio of T-bet to Eomes, leading to the ultimate control of this chronic viral infection.
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Ribhu
authors.initials: R
authors.lastname: Nayar
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Schutten
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Sonal
authors.initials: S
authors.lastname: Jangalwe
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Durost
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Kenney
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: James M
authors.initials: JM
authors.lastname: Conley
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Keith
authors.initials: K
authors.lastname: Daniels
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.affiliation: Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01605, United States of America.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Berg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D006224:Cricetinae; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D008217:Lymphocytic choriomeningitis virus / Q000502:physiology*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism*; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D000099218:Interferon Regulatory Factor-4; C491198:Eomes protein, mouse