A new mTOR-dependent, Akt-independent pathway differentiates the migratory behavior of regulatory and conventional T cells (CAM1P.235)

The vitamin A metabolite all-trans retinoic acid (ATRA) induces a gut-homing phenotype in activated CD4+ conventional T cells (Tconv) by upregulating the integrin α4β7 and the chemokine receptor CCR9. We report that in contrast to mouse Tconv, only half of regulatory T cells (Treg) upregulate CCR9 when stimulated in presence of ATRA, even though Tconv and Treg express identical levels of receptor (RAR). The bimodal distribution of CCR9+ versus CCR9- Treg subsets is not associated to differences in proliferation, level of FoxP3 expression, or segregation between thymic-derived and induced Treg. Furthermore, exposure to the mTOR inhibitor rapamycin suppresses upregulation of both CCR9+ and α4β7 on Treg, an inhibitory effect not evident in Tconv. This suggests that ATRA-induced upregulation of CCR9 and α4β7 on Treg is dependent on activation of an mTOR signaling pathway. This mTOR involvement is independent of Akt activity, since specific inhibition of Akt or its downstream target GSK-3B did not prevent CCR9 expression. Additionally, Rictor-/- Treg (that lack mTORC2) showed unaltered expression of CCR9 compared to WT control, suggesting participation of mTORC1 or another mTOR complex. These findings reveal a novel difference between ATRA signaling and chemokine receptor induction in Treg versus Tconv, and provide a framework via which the migratory behavior of Treg versus Tconv can be differentially influenced for therapeutic purposes.