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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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.).
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.
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.
Brightfield time-lapse microscopy of Ptcd lymph node cells as described in Supplementary Video 2.
Brightfield time-lapse microscopy of Coro1a−/− lymph node cells as described in Supplementary Video 2.
About this article
Cell Communication and Signaling (2015)