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.
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Authors | Lawrence R Shiow, David W Roadcap, Kenneth Paris, Susan R Watson, Irina L Grigorova, Tonya Lebet, Jinping An, Ying Xu, Craig N Jenne, Niko Föger, Ricardo U Sorensen, Christopher C Goodnow, James E Bear, Jennifer M Puck, Jason G Cyster |
Journal | Nature immunology
(Nat Immunol)
Vol. 9
Issue 11
Pg. 1307-15
(Nov 2008)
ISSN: 1529-2916 [Electronic] United States |
PMID | 18836449
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Actin-Related Protein 2-3 Complex
- Actins
- Microfilament Proteins
- coronin proteins
- Glutamic Acid
- Lysine
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Topics |
- Actin-Related Protein 2-3 Complex
(antagonists & inhibitors, metabolism)
- Actins
(metabolism)
- Alleles
- Amino Acid Substitution
- Animals
- Cell Movement
(genetics, immunology)
- Cell Shape
- Female
- Glutamic Acid
(genetics)
- Humans
- Lysine
(genetics)
- Male
- Mice
- Mice, Inbred ICR
- Mice, Knockout
- Microfilament Proteins
(genetics, physiology)
- Mutation
- Severe Combined Immunodeficiency
(genetics, immunology)
- T-Lymphocytes
(immunology)
- Thymus Gland
(immunology)
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