Lysophosphatidylserine suppression of T-cell activation via GPR174 requires Gαs proteins

G protein-coupled receptors regulate diverse aspects of T-cell activity and effector function. Recently, we showed that GPR174 mediates the suppression of T-cell proliferation in vitro induced by the polar lipid lysophosphatidylserine (LysoPS). Here, we investigated the in vivo activity of this pathway and characterized the mechanisms involved. Using in vivo models of T-cell proliferation induced by sublethal irradiation or regulatory T-cell depletion, we show that GPR174 expression can constrain T-cell proliferation. In vitro experiments established that Gαs G proteins are needed for LysoPS/GPR174-mediated suppression of T-cell proliferation. Mechanistically, LysoPS acts via GPR174 and Gαs to suppress IL-2 production by activated T cells and limit upregulation of the activation markers CD25 and CD69. Together, our findings identify GPR174 as an abundantly expressed Gαs-dependent receptor that can negatively regulate naive T-cell activation. See also: News and Commentary by Robert & Mackay.