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

Abstract

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.

Immunology & Cell Biology's top 10 original research articles 2017–2018

“…Instead, invariant NKT cells were found to highly express GPR65 and contribute to the exacerbated disease when GPR65 was absent . Similar to GPR65, GPR174 was found to regulate T‐cell activation through the Gαs subunit in response to stimulation by lysophosphatidylserine, a phosphotidylserine metabolite . Given the abundant expression of GPR174, this work by Barnes and Cyster highlights a potential regulatory target to modulate conventional T‐cell activation in a therapeutic setting .…”

“…Barnes & Cyster. Lysophosphatidylserine suppression of T‐cell activation via GPR174 requires Gαs proteins Zinser et al .…”

“…The cellular signals that regulate lymphocyte activation, differentiation and survival are also well represented in the top ICB articles and include the contribution of G protein‐coupled receptors (GPR65 and GPR174) in suppressing T‐cell activation and autoimmune activity, the integration of Notch and cytokine signals in generating γδ T‐cell subsets, and the role of the immunoproteosome subunit LMP2 in promoting lymphocyte survival . Wirasinha et al .…”

“…2 Similar to GPR65, GPR174 was found to regulate T-cell activation through the Gas subunit in response to stimulation by lysophosphatidylserine, a phosphotidylserine metabolite. 5 Given the abundant expression of GPR174, this work by Barnes and Cyster highlights a potential regulatory target to modulate conventional T-cell activation in a therapeutic setting. 5 Using fetal thymus organ culture, Zarin et al explore the signaling requirements for the generation of IFN-c-and IL-17-producing cd T-cell subsets and how these signals integrate into a differentiation program.…”

“…5 Given the abundant expression of GPR174, this work by Barnes and Cyster highlights a potential regulatory target to modulate conventional T-cell activation in a therapeutic setting. 5 Using fetal thymus organ culture, Zarin et al explore the signaling requirements for the generation of IFN-c-and IL-17-producing cd T-cell subsets and how these signals integrate into a differentiation program. 10 Finally, to investigate the signals promoting the survival of lymphocytes, Zanker et al discovered that LMP2 enhances survival by enabling the degradation of the pro-apoptotic protein, BIM, and thus revealing an additional role for the immunoproteome in maintaining adaptive immunity.…”