Article abstract
Nature Immunology 9, 1307 - 1315 (2008)
Published online: 5 October 2008 | doi:10.1038/ni.1662
The actin regulator coronin 1A is mutant in a thymic egress–deficient mouse strain and in a patient with severe combined immunodeficiency
Lawrence R Shiow1,2,3, David W Roadcap5, Kenneth Paris7, Susan R Watson2, Irina L Grigorova1,2, Tonya Lebet2,4, Jinping An1,2, Ying Xu1,2, Craig N Jenne1,2, Niko Föger8, Ricardo U Sorensen7, Christopher C Goodnow6, James E Bear5, Jennifer M Puck3,4 & Jason G Cyster1,2,3
Abstract
Mice carrying the recessive locus for peripheral T cell deficiency (Ptcd) have a block in thymic egress, but the mechanism responsible is undefined. Here we found that Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking and irregularly shaped protrusions. Characterization of the Ptcd locus showed a point substitution of lysine for glutamic acid at position 26 in the actin regulator coronin 1A that enhanced its inhibition of the actin regulator Arp2/3 and resulted in its mislocalization from the leading edge of migrating T cells. The discovery of another coronin 1A mutant during an N-ethyl-N-nitrosourea-mutagenesis screen for T cell–lymphopenic mice prompted us to evaluate a T cell–deficient, B cell–sufficient and natural killer cell–sufficient patient with severe combined immunodeficiency, whom we found had mutations in both CORO1A alleles. Our findings establish a function for coronin 1A in T cell egress, identify a surface of coronin involved in Arp2/3 regulation and demonstrate that actin regulation is a biological process defective in human and mouse severe combined immunodeficiency.
- Howard Hughes Medical Institute, San Francisco, California 94143, USA
- Department of Microbiology and Immunology, San Francisco, California 94143, USA
- Biomedical Sciences Graduate Program, San Francisco, California 94143, USA
- Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, California 94143, USA.
- Lineberger Comprehensive Cancer Center and Department of Cell and Developmental Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
- John Curtin School of Medical Research, The Australian National University, Canberra ACT 2601, Australia.
- Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, Louisiana 70118, USA.
- Department of Immunology and Cell Biology, Leibniz Center for Medicine and Biosciences, Borstel 23845, Germany.
Correspondence to: Jason G Cyster1,2,3 e-mail: jason.cyster@ucsf.edu
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