Introduction Annexin-1 (Anx-A1) is an anti-inflammatory protein that plays an important homeostatic role in innate immunity (1-2), however its potential actions in the modulation of adaptive immunity have never been explored. In this study we investigated the role of exogenous and endogenous Anx-A1 in T cell activation and differentiation and its role in the development of Th1/Th2-driven diseases. Results Addition of human recombinant (hr)Anx-A1 to stimulated T cells augmented anti-CD3/CD28-mediated CD25 and CD69 expression and cell proliferation. This effect was paralleled by increased NF-κB, AP-1 and NFAT activation and preceded by a rapid T cell receptor (TCR)-induced externalization of the Anx-A1 receptor. Conversely, analysis of T cell responses in Anx-A1 knock-out cells showed a decrease in cell activation and proliferation as well as in the activation of the above mentioned transcription factors. Interestingly, differentiation of naïve T cells in presence of hrAnx-A1 increased skewing in Th1 cells whereas Anx-A1 deficient T cells demonstrated an increased Th2 phenotype compared to cells from control littermates. In the collagen induced arthritis model (Th1-driven model) treatment of mice with hrAnx-A1 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 upregulation of Anx-A1 expression (3). Finally, analysis of allergic response in Anx-A1 knock-out mice using a mouse model of ovalbumin-induced allergic peritonitis (Th2-driven model) demonstrated an exacerbated Th2 response i.e. increased number of T cells and eosinophil at site of inflammation compared to the wild type littermates. Conclusions Together these results demonstrate that Anx-A1 acts as a molecular ‘tuner’ of TCR signalling 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 etiological factor.