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The actin regulator coronin 1A is mutant in a thymic egress–deficient mouse strain and in a patient with severe combined immunodeficiency

Nature Immunology volume 9, pages 1307–1315 (2008)Cite this article

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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Figure 1: Ptcd T cells have an intrinsic migration defect.
Figure 2: Ptcd T cells are defective in lymph node trafficking.
Figure 3: Coro1a is mutated at the Ptcd locus.
Figure 4: The ENU mutant Koy is a Coro1A hypomorph.
Figure 5: Allelic comparison of cell survival, F-actin accumulation and Ca2+ flux.
Figure 6: The E26K substitution alters the cellular distribution of Coro1A and the regulation of Arp2/3 by Coro1A.
Figure 7: Deficiency of Coro1A in a T−B+NK+ patient with SCID.

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Acknowledgements

We thank the patient with SCID and her family; M. Anderson, P. Beemiller, S. Cheung, G. Cinamon, M. Krummel, T. Phan, H. Phee and A. Weiss for discussions; and D. Schafer (University of Virginia) for advice and reagents related to the pyrene actin assay. Supported by the University of California, San Francisco Medical Scientist Training Program (L.R.S.), Genentech Sandler Family Foundation (L.R.S.), the US Immunodeficiency Network (J.M.P.), the Jeffrey Modell Foundation (J.M.P.), the Howard Hughes Medical Institute (J.G.C.) and the National Institutes of Health (C.C.G., J.E.B. and J.G.C.).

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Authors and Affiliations

  1. Howard Hughes Medical Institute, San Francisco, 94143, California, USA

    Lawrence R Shiow, Irina L Grigorova, Jinping An, Ying Xu, Craig N Jenne & Jason G Cyster

  2. Department of Microbiology and Immunology, San Francisco, 94143, California, USA

    Lawrence R Shiow, Susan R Watson, Irina L Grigorova, Tonya Lebet, Jinping An, Ying Xu, Craig N Jenne & Jason G Cyster

  3. Biomedical Sciences Graduate Program, San Francisco, 94143, California, USA

    Lawrence R Shiow, Jennifer M Puck & Jason G Cyster

  4. Department of Pediatrics and Institute for Human Genetics, University of California San Francisco, San Francisco, 94143, California, USA

    Tonya Lebet & Jennifer M Puck

  5. Lineberger Comprehensive Cancer Center and Department of Cell and Developmental Biology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    David W Roadcap & James E Bear

  6. John Curtin School of Medical Research, The Australian National University, Canberra, 2601, ACT, Australia

    Christopher C Goodnow

  7. Department of Pediatrics, Louisiana State University Health Sciences Center and Children's Hospital, New Orleans, 70118, Louisiana, USA

    Kenneth Paris & Ricardo U Sorensen

  8. Department of Immunology and Cell Biology, Leibniz Center for Medicine and Biosciences, Borstel, 23845, Germany

    Niko Föger

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Correspondence to Jason G Cyster.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9 and Supplementary Table 1 (PDF 1616 kb)

Supplementary Movie 1

Comparison of two-photon time-lapse microscopy of control (left) or Ptcd (right) cells labeled in red and wild-type GFP cells in green migrating in the T zone of an explanted lymph node. Yellow tracks generated to aid visualization of representative wild-type GFP cells and white tracks of control (left) or Ptcd (right) cells. (MPG 5465 kb)

Supplementary Movie 2

Brightfield time-lapse microscopy of wildtype lymph node cells on ICAM-coated coverslips in 1 ug/mL CCL21, followed by fluorescent exposure to identify T cells (blue), B cells (red) and dead cells (pink). Tracks generated to aid visualization of migrating T cells. Movie is optimally viewed at full-screen. (MPG 7966 kb)

Supplementary Movie 3

Brightfield time-lapse microscopy of Ptcd lymph node cells as described in Supplementary Video 2. (MPG 8043 kb)

Supplementary Movie 4

Comparison of brightfield time-lapse microscopy of wild-type and Ptcd T cells cropped from Supplementary Video 2 and 3. (MPG 448 kb)

Supplementary Movie 5

Brightfield time-lapse microscopy of Coro1a−/− lymph node cells as described in Supplementary Video 2. (MPG 7882 kb)

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Shiow, L., Roadcap, D., Paris, K. et al. The actin regulator coronin 1A is mutant in a thymic egress–deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol 9, 1307–1315 (2008). https://doi.org/10.1038/ni.1662

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