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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1095-1102.
Prepublished online as a Blood First Edition Paper on September 28, 2006; DOI 10.1182/blood-2006-05-022798.
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IMMUNOBIOLOGY
Annexin-1 modulates T-cell activation and differentiation
Fulvio D'Acquisto1,
Ahmed Merghani1,
Emilio Lecona1,
Guglielmo Rosignoli1,
Karim Raza2,
Christopher D. Buckley2,
Roderick J. Flower1, and
Mauro Perretti1
1 William Harvey Research Institute, Bart's and The London, Queen Mary School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom;
2 Division of Immunity and Infection, MRC Centre for Immune Regulation, University of Birmingham, Edgbaston, United Kingdom
Annexin-1 is an anti-inflammatory protein that plays an important homeostatic role in innate immunity; however, its potential actions in the modulation of adaptive immunity have never been explored. Although inactive by itself, addition of annexin-1 to stimulated T cells augmented anti-CD3/CD28-mediated CD25 and CD69 expression and cell proliferation. This effect was paralleled by increased nuclear factor- B (NF-B), nuclear factor of activated T cells (NFATs), and activator protein-1 (AP-1) activation and preceded by a rapid T-cell receptor (TCR)–induced externalization of the annexin-1 receptor. Interestingly, differentiation of naive T cells in the presence of annexin-1 increased skewing in Th1 cells; in the collagen-induced arthritis model, treatment of mice with annexin-1 during the immunization phase exacerbated signs and symptoms at disease onset. Consistent with these findings, blood CD4+ cells from patients with rheumatoid arthritis showed a marked up-regulation of annexin-1 expression. Together these results demonstrate that annexin-1 is a molecular "tuner" of TCR signaling and suggest this protein might represent a new target for the development of drugs directed to pathologies where an unbalanced Th1/Th2 response or an aberrant activation of T cells is the major etiologic factor.
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