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Mol Cell Biol. 2016 Sep 6. pii: MCB.00281-16. [Epub ahead of print]

T cell immune deficiency in zap70 mutant zebrafish.

Author information

1
Molecular Pathology, Massachusetts General Hospital, Charlestown, MA, USA Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA Cancer Center, Massachusetts General Hospital, Charlestown, MA, USA Harvard Stem Cell Institute, Cambridge MA, USA.
2
Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD, USA.
3
Harvard Stem Cell Institute, Cambridge MA, USA Harvard University, Cambridge, MA.
4
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA Department of Genetics, Harvard Medical School, Boston, MA, USA.
5
Izaak Walton Killam Health Center, Dalhousie University, Halifax, Nova Scotia, Canada.
6
Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
7
Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD, USA dlangenau@mgh.harvard.edu flyingfish2@nih.gov.
8
Molecular Pathology, Massachusetts General Hospital, Charlestown, MA, USA Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA Cancer Center, Massachusetts General Hospital, Charlestown, MA, USA Harvard Stem Cell Institute, Cambridge MA, USA dlangenau@mgh.harvard.edu flyingfish2@nih.gov.

Abstract

The zeta-chain (TCR) associated protein kinase 70kDa (ZAP70) is required for T-cell activation. ZAP70 deficiencies in humans and null mutations in mice lead to severe combined immunodeficiency. Here, we describe a zap70 loss-of-function mutation in zebrafish (zap70y442) that was created using TALENs. In contrast to what has been reported in morphant zebrafish, zap70y442 homozygous mutant zebrafish displayed normal development of blood and lymphatic vasculature. Hematopoietic cell development was also largely unaffected in mutant larvae. However, mutant fish had reduced lck:GFP+ thymic T cells by 5 days post-fertilization that persisted into adult stages. Morphological analysis, RNA sequencing and single-cell gene expression profiling of whole kidney marrow cells of adult fish revealed complete loss of mature T cells in zap70y442 mutant animals. T cell immunodeficiency was confirmed through transplantation of unmatched normal and malignant donor cells into zap70y442 mutant zebrafish, with T cell loss being sufficient for robust allogeneic cell engraftment. zap70 mutant zebrafish show remarkable conservation of immune cell dysfunction as found in mice and humans and will serve as a valuable model to study zap70 immunodeficiency.

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