Submitted July 13, 2006
Accepted October 12, 2006
Altered activation of AKT is required for the suppressive function of human CD4+CD25+ T regulatory cells
Natasha K Crellin, Rosa V Garcia, and Megan K Levings*
University of British Columbia, Canada
Vancouver Coastal Health Research Institute, Canada
* Corresponding author; email: mlevings{at}interchange.ubc.ca.
Suppression by T regulatory cells (Tregs) is a major mechanism by which the immune system controls responses to self and non-harmful foreign proteins. Although there are many different types of Treg cells, the best characterized are those that constitutively express cell-surface IL-2R
(CD25). We investigated whether altered TCR-mediated signaling in pure populations of ex vivo human CD4+CD25+ Tregs might underlie their unique phenotype, including hyporesponsiveness to T cell receptor mediated activation and lack of cytokine production. CD4+CD25+ Tregs displayed a consistent defect in phosphorylation of AKT at serine 473, and reduced phosphorylation of the AKT substrates FOXO and S6. Restoration of AKT activity via lenti-viral mediated expression of an inducibly active form of the kinase revealed that reduced activity of this pathway was necessary for the suppressive function of CD4+CD25+ Tregs. These data represent the first demonstration of a causal association between altered signaling and the function of CD4+CD25+ Tregs. Moreover, we have created the first system allowing inducible abrogation of suppression through manipulation of the suppressor cells. This system will be a powerful tool to further study the mechanism(s) of suppression by CD4+CD25+ Tregs.
