title: Heme exporter FLVCR is required for T cell development and peripheral survival.
abstract: All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid cycle intermediate succinyl CoA for incorporation into hemoproteins, such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however, much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12-transmembrane domain surface protein that exports heme from cells, and it was shown to be required for erythroid development. In this article, we show that deletion of Flvcr in murine hematopoietic precursors caused a complete block in αβ T cell development at the CD4(+)CD8(+) double-positive stage, although other lymphoid lineages were not affected. Moreover, FLVCR was required for the proliferation and survival of peripheral CD4(+) and CD8(+) T cells. These studies identify a novel and unexpected role for FLVCR, a major facilitator superfamily metabolite transporter, in T cell development and suggest that heme metabolism is particularly important in the T lineage.
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Mary
authors.initials: M
authors.lastname: Philip
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195;
authors.forename: Scott A
authors.initials: SA
authors.lastname: Funkhouser
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195;
authors.forename: Edison Y
authors.initials: EY
authors.lastname: Chiu
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195;
authors.forename: Susan R
authors.initials: SR
authors.lastname: Phelps
authors.affiliation: Genomics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA 98109;
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Delrow
authors.affiliation: University of Utah Metabolomics Core Facility, Salt Lake City, UT 84132; and.
authors.forename: James
authors.initials: J
authors.lastname: Cox
authors.affiliation: Department of Immunology, University of Washington, Seattle, WA 98109.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Fink
authors.affiliation: Division of Hematology, University of Washington, Seattle, WA 98195; janabk@u.washington.edu.
authors.forename: Janis L
authors.initials: JL
authors.lastname: Abkowitz
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002454:Cell Differentiation / Q000276:immunology*; D002469:Cell Separation; D002470:Cell Survival / Q000276:immunology; D005434:Flow Cytometry; D006418:Heme / Q000276:immunology*; D026901:Membrane Transport Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D011991:Receptors, Virus / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C526650:Flvcr1 protein, mouse; D026901:Membrane Transport Proteins; D011991:Receptors, Virus; D006418:Heme