title: Divergent generation of heterogeneous memory CD4 T cells.
abstract: Mechanisms for the generation of memory CD4 T cells and their delineation into diverse subsets remain largely unknown. In this study, we demonstrate in two Ag systems, divergent generation of heterogeneous memory CD4 T cells from activated precursors in distinct differentiation stages. Specifically, we show that influenza hemagglutinin- and OVA-specific CD4 T cells activated for 1, 2, and 3 days, respectively, exhibit gradations of differentiation by cell surface phenotype, IFN-gamma production, and proliferation, yet all serve as direct precursors for functional memory CD4 T cells when transferred in vivo into Ag-free mouse hosts. Using a conversion assay to track the immediate fate of activated precursors in vivo, we show that day 1- to 3-activated cells all rapidly convert from an activated phenotype (CD25(high)IL-7R(low)CD44(high)) to a resting memory phenotype (IL-7R(high)CD25(low)CD44(high)) 1 day after antigenic withdrawal. Paradoxically, stable memory subset delineation from undifferentiated (day 1- to 2-activated) precursors was predominantly an effector memory (CD62L(low)) profile, with an increased proportion of central memory (CD62L(high)) T cells arising from more differentiated (day 3-activated) precursors. Our findings support a divergent model for generation of memory CD4 T cells directly from activated precursors in multiple differentiation states, with subset heterogeneity maximized by increased activation and differentiation during priming.
authors.affiliation: Department of Surgery, Division of Transplantation, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA.
authors.forename: Vaishali R
authors.initials: VR
authors.lastname: Moulton
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Bushar
authors.forename: David B
authors.initials: DB
authors.lastname: Leeser
authors.forename: Deepa S
authors.initials: DS
authors.lastname: Patke
authors.forename: Donna L
authors.initials: DL
authors.lastname: Farber
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010047:Ovalbumin / Q000276:immunology; D013234:Stem Cells / Q000166:cytology / Q000276:immunology; D013997:Time Factors
chemical_list: D018984:Epitopes, T-Lymphocyte; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D010047:Ovalbumin