title: CD4+ T cell effector commitment coupled to self-renewal by asymmetric cell divisions.
abstract: Upon infection, an activated CD4+T cell produces terminally differentiated effector cells and renews itself for continued defense. In this study, we show that differentiation and self-renewal arise as opposing outcomes of sibling CD4+T cells. After influenza challenge, antigen-specific cells underwent several divisions in draining lymph nodes (LN; DLNs) while maintaining expression of TCF1. After four or five divisions, some cells silenced, whereas some cells maintained TCF1 expression. TCF1-silenced cells were T helper 1-like effectors and concentrated in the lungs. Cells from earliest divisions were memory-like and concentrated in nondraining LN. TCF1-expressing cells from later divisions in the DLN could self-renew, clonally yielding a TCF1-silenced daughter cell as well as a sibling cell maintaining TCF1 expression. Some TCF1-expressing cells in DLNs acquired an alternative, follicular helper-like fate. Modeled differentiation experiments in vitro suggested that unequal PI3K/mechanistic target of rapamycin signaling drives intraclonal cell fate heterogeneity. Asymmetric division enables self-renewal to be coupled to production of differentiated CD4+effector T cells during clonal selection.
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Simone A
authors.identifier: 0000-0002-9070-1796
authors.initials: SA
authors.lastname: Nish
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.|Department of Surgery, Columbia University Medical Center, New York, NY 10032.
authors.forename: Kyra D
authors.identifier: 0000-0001-7979-076X
authors.initials: KD
authors.lastname: Zens
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Radomir
authors.initials: R
authors.lastname: Kratchmarov
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Wen-Hsuan W
authors.identifier: 0000-0002-5414-7900
authors.initials: WW
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: William C
authors.initials: WC
authors.lastname: Adams
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Yen-Hua
authors.identifier: 0000-0002-8880-5684
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Bonnie
authors.identifier: 0000-0003-0653-863X
authors.initials: B
authors.lastname: Yen
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Nyanza J
authors.identifier: 0000-0002-9707-2283
authors.initials: NJ
authors.lastname: Rothman
authors.affiliation: T-Cell Biology and Development Unit, Laboratory of Genome Integrity, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Avinash
authors.initials: A
authors.lastname: Bhandoola
authors.affiliation: Department of Microbiology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
authors.affiliation: Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032.|Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032.|Department of Surgery, Columbia University Medical Center, New York, NY 10032.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
authors.affiliation: Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, New York, NY 10032 sr2978@cumc.columbia.edu.|Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032.
authors.forename: Steven L
authors.identifier: 0000-0002-1635-8619
authors.initials: SL
authors.lastname: Reiner
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002455:Cell Division; D002478:Cells, Cultured; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000032:analysis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000502:physiology
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C496488:Hnf1a protein, mouse; C546843:mTOR protein, mouse