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Molecular and Cellular Biology, December 2005, p. 11145-11155, Vol. 25, No. 24
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.24.11145-11155.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Targeted Deletion of Integrin-Linked Kinase Reveals a Role in T-Cell Chemotaxis and Survival

Emerson Liu,1,{dagger} Sumita Sinha,1,{dagger} Christine Williams,2 Marcoli Cyrille,1 Eric Heller,1 Scott B. Snapper,3 Katia Georgopoulos,3 Rene St-Arnaud,4 Thomas Force,5 Shoukat Dedhar,6 and Robert E. Gerszten1*

Center for Immunology and Inflammatory Diseases & Cardiology Division, Massachusetts General Hospital, Charlestown, Massachusetts, and Harvard Medical School, Boston, Massachusetts,1 Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts, and Harvard Medical School, Boston, Massachusetts,2 Gastrointestinal Unit, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts,3 Shriners Hospital and McGill University, Montreal, Quebec, Canada,4 Molecular Cardiology Research Institute, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts,5 Department of Biochemistry and Molecular Biology, University of British Columbia, and Jack Bell Cancer Centre at Vancouver General Hospital and Health Service Center, Vancouver, British Columbia, Canada6

Received 17 August 2005/ Accepted 7 September 2005

Integrin-linked kinase (ILK) is a serine/threonine kinase that is important in cell-matrix interactions and cell signaling. To examine the role of ILK in leukocyte trafficking and survival, we generated T cell-specific ILK knockouts by breeding ILKflox/flox mice to transgenic mice expressing Cre recombinase under control of the Lck proximal promoter. Thymic T cells from Lck-Cre+/ILKflox/flox mice had a marked reduction (>95%) in ILK protein levels. Thymic cellularity was comparable in 3- to 4-week-old mice, but a threefold diminution of thymic T cells became evident by 6 to 8 weeks of age in the T cell-specific ILK knockout mice due to increased cell death of double-positive (DP) T cells. Analysis of peripheral T cells by quantitative PCR and by breeding Lck-Cre+/ILKflox/flox mice to a YFP-transgenic reporter strain demonstrated an approximate 20-fold enrichment of ILK-competent cells, suggesting these cells have a competitive advantage in trafficking to and/or survival in peripheral lymphatic organs. We explored mechanisms related to altered cell trafficking and survival that might explain the decreases in thymic cellularity and enrichment for ILK-competent cells in the spleen and lymph nodes. We observed a >50% reduction in chemotaxis of ILK-deficient T cells to the chemokines CXCL12 (stromal cell-derived factor [SDF]-1{alpha}) and CCL19 (macrophage inflammatory protein [MIP]-3ß), as well as enhanced apoptosis of ILK-deficient cells upon stress. Signaling studies in ILK-deficient T cells demonstrated diminished phosphorylation of Akt on the activating phosphorylation site, Ser 473, and a concordant decrease in Akt kinase activity following stimulation with the chemokine SDF-1. Rac1 activation was also markedly diminished in ILK-deficient T cells following chemokine stimulation. These data extend the role of ILK to immune-cell trafficking and survival via modulation of Akt- and Rac-dependent substrates, and have implications for cell recruitment in both homeostatic and pathological processes.

* Corresponding author. Mailing address: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East—8307, 149 13th Street, Charlestown, MA 02129. Phone: (617) 724-8322. Fax: (617) 726-5651. E-mail: rgerszten{at}partners.org.

{dagger} Contributed equally to this work.

Molecular and Cellular Biology, December 2005, p. 11145-11155, Vol. 25, No. 24
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.24.11145-11155.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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