title: Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners.
abstract: In a primitive chordate model of natural chimerism, one chimeric partner is often eliminated in a process of allogeneic resorption. Here, we identify the cellular framework underlying loss of tolerance to one partner within a natural Botryllus schlosseri chimera. We show that the principal cell type mediating chimeric partner elimination is a cytotoxic morula cell (MC). Proinflammatory, developmental cell death programs render MCs cytotoxic and, in collaboration with activated phagocytes, eliminate chimeric partners during the "takeover" phase of blastogenic development. Among these genes, the proinflammatory cytokine IL-17 enhances cytotoxicity in allorecognition assays. Cellular transfer of FACS-purified MCs from allogeneic donors into recipients shows that the resorption response can be adoptively acquired. Transfer of 1 × 10(5) allogeneic MCs eliminated 33 of 78 (42%) recipient primary buds and 20 of 76 (20.5%) adult parental adult organisms (zooids) by 14 d whereas transfer of allogeneic cell populations lacking MCs had only minimal effects on recipient colonies. Furthermore, reactivity of transferred cells coincided with the onset of developmental-regulated cell death programs and disproportionately affected developing tissues within a chimera. Among chimeric partner "losers," severe developmental defects were observed in asexually propagating tissues, reflecting a pathologic switch in gene expression in developmental programs. These studies provide evidence that elimination of one partner in a chimera is an immune cell-based rejection that operates within histocompatible pairs and that maximal allogeneic responses involve the coordination of both phagocytic programs and the "arming" of cytotoxic cells.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305; dcorey@stanford.edu irv@stanford.edu.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Corey
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Benyamin
authors.initials: B
authors.lastname: Rosental
authors.affiliation: Department of Applied Physics, Stanford University, Stanford, CA 94305; Department of Bioengineering, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Mark
authors.initials: M
authors.lastname: Kowarsky
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Rahul
authors.initials: R
authors.lastname: Sinha
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Ishizuka
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Palmeri
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Applied Physics, Stanford University, Stanford, CA 94305; Department of Bioengineering, Stanford University, Stanford, CA 94305; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305;
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Quake
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Hopkins Marine Station, Stanford University, Pacific Grove, CA 93950;
authors.forename: Ayelet
authors.initials: A
authors.lastname: Voskoboynik
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305; Department of Pathology, Hopkins Marine Station, Stanford University, Pacific Grove, CA 93950; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, CA 94305 dcorey@stanford.edu irv@stanford.edu.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Weissman
mesh_terms: D000818:Animals; D001483:Base Sequence; D016923:Cell Death; D009028:Morula / Q000166:cytology* / Q000637:transplantation; D018183:Transplantation Chimera; D014561:Urochordata / Q000166:cytology / Q000235:genetics / Q000276:immunology*
keywords: apoptosis; histocompatibility; inflammation; innate immunity; macrophages