Developmental cell death programs license cytotoxic cells to eliminate histocompatible partners

Daniel M. Corey, Benyamin Rosental, Mark Kowarsky, Rahul Sinha, Katherine J. Ishizuka, Karla J. Palmeri, Stephen R. Quake, Ayelet Voskoboynik, Irving L. Weissman

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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 × 105 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.

Original languageEnglish
Pages (from-to)6520-6525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number23
DOIs
StatePublished - 7 Jun 2016
Externally publishedYes

Keywords

  • Apoptosis
  • Histocompatibility
  • Inflammation
  • Innate immunity
  • Macrophages

ASJC Scopus subject areas

  • General

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