miR-155 regulates lymphocyte homeostasis in LAT mutant mice (LYM4P.749)

LAT Y136F mutant mice carry a tyrosine-to-phenylalanine mutation in the LAT adapter gene that leads to a lymphoproliferative disease (LPD) initiated by CD4+ helper T cells. In a screen to detect microRNAs (miRs) specifically regulated in LAT Y136F CD4+ T cells, we found that levels of miR-155 were higher in these T cells than in other proliferating CD4+ T cells from wild type C57BL/6 mice. In order to reveal a potential role of miR-155 in LAT Y136F LPD, we crossed LAT Y136F mice to miR-155-deficient mice yielding double mutant (DM) mice. This resulted in a delay and decreased severity of LPD in DM mice. DM CD4+ T cells showed equal or higher proliferation rates than CD4+ T cells from age-matched LAT Y136F mice, however levels of apoptosis in DM CD4+ T cells were higher. One direct target downregulated by miR-155 is the forkhead transcription factor FOXO3a. In DM T cells, increased expression of FOXO3a led to accumulation of the pro-apoptotic factor Bim and enhanced apoptosis. In addition, elevated Pak1 kinase activity in DM T cells led to activation of Jnk leading to phosphorylation of FOXO3a, FOXO3a nuclear translocation and increased FOXO3a activity. Consequently, direct and indirect effects of miR-155 on FOXO3a led to an increase in Bim-mediated apoptosis and decreased LPD in DM mice. Investigation of downstream targets of miR-155 has led to new information on signaling molecules that control LPD and lymphocyte homeostasis.