HS1 functions as an essential actin-regulatory adaptor protein at the immune synapse.
HS1, the leukocyte-specific homolog of cortactin, regulates F-actin in vitro and is phosphorylated in response to TCR ligation, but its role in lymphocyte activation has not been addressed. We demonstrate that HS1-deficient T cells fail to accumulate F-actin at the immune synapse (IS) and, upon TCR ligation, form actin-rich structures that are disordered and unstable. Early TCR activation events are intact in these cells, but Ca2+ influx and IL-2 gene transcription are defective. Importantly, HS1 tyrosine phosphorylation is required for its targeting to the IS and for its function in regulating actin dynamics and IL-2 promoter activity. Phosphorylation also links HS1 to multiple signaling proteins, including Lck, PLCgamma1, and Vav1, and is essential for the stable recruitment of Vav1 to the IS. Taken together, our studies show that HS1 is indispensable for signaling events leading to actin assembly and IL-2 production during T cell activation.
Gomez
Timothy S
TS
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
McCarney
Sean D
SD
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Carrizosa
Esteban
E
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Labno
Christine M
CM
Department of Pathology, University of Chicago, Chicago, Illinois 60637.
Comiskey
Erin O
EO
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104.
Nolz
Jeffrey C
JC
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905.
Zhu
Peimin
P
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104.
Freedman
Bruce D
BD
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania 19104.
Clark
Marcus R
MR
Department of Medicine, University of Chicago, Chicago, Illinois 60637.
Rawlings
David J
DJ
Department of Pediatrics, Department of Immunology, University of Washington School of Medicine, Seattle, Washington 98195.
Billadeau
Daniel D
DD
Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905; Division of Oncology Research, Mayo Clinic College of Medicine, Rochester, Minnesota 55905. Electronic address: billadeau.daniel@mayo.edu.
Burkhardt
Janis K
JK
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania 19104. Electronic address: jburkhar@mail.med.upenn.edu.
D000199:Actins / Q000032:analysis / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001798:Blood Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000819:agonists / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D001798:Blood Proteins; C061909:HCLS1 protein, human; D007376:Interleukin-2; D051567:Proto-Oncogene Proteins c-vav; D011948:Receptors, Antigen, T-Cell; C496619:Vav1 protein, mouse; D014443:Tyrosine; D051966:Phospholipase C gamma; D002118:Calcium