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

  • Nikolaos Paschalidis
    ,
  • Anthony Huggins
    ,
  • Nicola J. Rowbotham
    ,
  • Anna L. Furmanski
    ,
  • Tessa Crompton
    ,
  • Roderick J. Flower
  • Queen Mary University of London
    ,
  • University College London
Research Output: Contribution to journal Article Peer-review

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 NFkappaB 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.

Publication Information

Output type

Research Output: Contribution to journal Article Peer-review

Original language

English

Pages from-to (Number of pages)

Pages 785-794 (10 pages)

Journal (Volume, Issue Number)

Cell Cycle (Volume 9, Issue 4)

Publication milestones

  • Published - 15/02/2010

Publication status

Published - 15/02/2010

ISSN

1538-4101

External Publication IDs

  • handle.net: 10547/623397
  • Scopus: 77953552941
  • PubMed: 20139728

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