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Targeted Deletion of Integrin-Linked Kinase Reveals a Role in T-Cell Chemotaxis and Survival.
- Source :
- Molecular & Cellular Biology; Dec2005, Vol. 25 Issue 24, p11145-11155, 11p, 2 Diagrams, 5 Graphs
- Publication Year :
- 2005
-
Abstract
- 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 ILK<superscript>flox/flox</superscript> mice to transgenic mice expressing Cre recombinase under control of the Lck proximal promoter. Thymic T cells from Lck-Cre<superscript>+</superscript>/ILK<superscript>flox/flox</superscript> 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<superscript>+</superscript>/ ILK<superscript>flox/flox</superscript> 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]-1α and CCL19 (macrophage inflammatory protein [MIP]-3β), 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- FOCAL adhesion kinase
INTEGRINS
T cells
TRANSGENIC mice
PROTEINS
CYTOKINES
Subjects
Details
- Language :
- English
- ISSN :
- 02707306
- Volume :
- 25
- Issue :
- 24
- Database :
- Complementary Index
- Journal :
- Molecular & Cellular Biology
- Publication Type :
- Academic Journal
- Accession number :
- 19297817
- Full Text :
- https://doi.org/10.1128/MCB.25.24.11145-11155.2005