|ZFIN ID: ZDB-PUB-160908-2|
T cell immune deficiency in zap70 mutant zebrafish
Moore, J.C., Mulligan, T.S., Torres Yordán, N., Castranova, D., Pham, V.N., Tang, Q., Lobbardi, R., Anselmo, A., Liwski, R.S., Berman, J.N., Sadreyev, R.I., Weinstein, B.M., Langenau, D.M.
|Source:||Molecular and cellular biology 36(23): 2868-2876 (Journal)|
|Registered Authors:||Berman, Jason, Castranova, Dan, Langenau, David, Moore, John, Mulligan, Tim, Pham, Van, Tang, Qin, Weinstein, Brant M.|
|PubMed:||27601584 Full text @ Mol. Cell. Biol.|
Moore, J.C., Mulligan, T.S., Torres Yordán, N., Castranova, D., Pham, V.N., Tang, Q., Lobbardi, R., Anselmo, A., Liwski, R.S., Berman, J.N., Sadreyev, R.I., Weinstein, B.M., Langenau, D.M. (2016) T cell immune deficiency in zap70 mutant zebrafish. Molecular and cellular biology. 36(23):2868-2876.
ABSTRACTThe 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.