Eur J Immunol. 2004 Apr;34(4):1217-27
Mayne M, Moffatt T, Kong H, McLaren PJ, Fowke KR, Becker KG, Namaka M, Schenck A, Bardoni B, Bernstein CN, Melanson M.
Department of Pharmacology and Therapeutics, University of Manitoba, Division of Neuroscience, St. Boniface Hospital Research Centre, Winnipeg, Canada
DNA microarray profiling of CD4(+) and CD8(+) cells from non-treated relapsing and remitting multiple sclerosis (MS) patients determined that the cytoplasmic binding partner of fragile X protein (CYFIP2, also called PIR121) was increased significantly compared to healthy controls.
Western analysis confirmed that CYFIP2 protein was increased approximately fourfold in CD4(+) cells from MS compared to inflammatory bowel disorder (IBD) patients or healthy controls.
Because CYFIP2 acts as part of a tetrameric complex that regulates WAVE1 activation we hypothesized that high levels of CYFIP2 facilitate T cell adhesion, which is elevated in MS patients.
Several findings indicated that increased levels of CYFIP2 facilitated adhesion.
First, adenoviral-mediated overexpression of CYFIP2 in Jurkat cells increased fibronectin-mediated adhesion.
Secondly, CYFIP2 knock-down experiments using antisense oligodeoxynucleotides reduced fibronectin-mediated binding in Jurkat and CD4(+) cells.
Thirdly, inhibition of Rac-1, a physical partner with CYFIP2 and regulator of WAVE1 activity, reduced fibronectin-mediated adhesion in Jurkat and CD4(+) cells.
Finally, inhibition of Rac-1 or reduction of CYFIP2 protein decreased fibronectin-mediated adhesion in CD4(+) cells from MS patients to levels similar to controls.
These studies suggest that overabundance of CYFIP2 protein facilitates increased adhesion properties of T cells from MS patients.