Annexin-1 modulates T-cell activation and differentiation.
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-kappaB (NF-kappaB), 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.
D'Acquisto
Fulvio
F
William Harvey Research Institute, Bart's and The London, Queen Mary School of Medicine and Dentistry, UK. f.dacquisto@qmul.ac.uk
Merghani
Ahmed
A
Lecona
Emilio
E
Rosignoli
Guglielmo
G
Raza
Karim
K
Buckley
Christopher D
CD
Flower
Roderick J
RJ
Perretti
Mauro
M
D000818:Animals; D017305:Annexin A1 / Q000502:physiology*; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D001168:Arthritis / Q000188:drug therapy / Q000209:etiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D007109:Immunity; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D051379:Mice; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*; D018417:Th1 Cells; D000099192:CD69 Antigens
D017305:Annexin A1; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D011948:Receptors, Antigen, T-Cell; D000099192:CD69 Antigens