Role of endogenous annexin-A1 in the regulation of thymocyte positive and negative selection

Abstract

We have recently shown that endogenous Annexin-A1 (AnxA1) plays a homeostatic regulatory role in mature t cells by modulating the strength of TCR signaling. In this study we investigated the role of endogenous AnxA1 in thymocyte maturation. Analysis of AnxA1-/- thymocyte populations at the immature CD4-CD8- double negative (DN) stage showed a proportional decrease in the DN1 and an increase in the DN3 subsets compared to control littermates. there were no significant differences in thymocyte numbers or proportions of CD4+ and CD8+ single positive (Sp) populations between Anx1-/- and AnxA1+/+ mice. However, when we crossed AnxA1-/- mice onto HY-TCR transgenic mice, we observed an increase in CD4+CD8+ double positive (DP) and CD4 Sp cells in male AnxA1-/-/HY-TCR compared to AnxA1+/+/HY-TCR. Conversely, female AnxA1-/-/HY-TCR mice showed an increase in DP and a decrease in CD8 (SP) cells compared to female AnxA1+/+/HY-TCR. Biochemical analysis of the signaling pathways responsible for these effects showed a decrease in anti-CD3-induced erk phosphorylation and NFκB activation in AnxA1-/- thymocytes compared to control littermates. together these findings demonstrate a role for endogenous AnxA1 in regulating both positive and negative selection of the TCR repertoire. these results suggest that targeting AnxA1 expression or function in t cells could represent a useful approach for the development of novel therapies for the treatment of autoimmune diseases. © 2010 Landes Bioscience.