Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function

Area of Science:

• Immunology
• Genetics
• Cell Biology

Background:

• The G-protein coupled receptor GPR174 is expressed in lymphocytes and has known immunoregulatory roles in mice.
• Its precise function in human immunity remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of GPR174 in human immune function.
• To identify clinical phenotypes associated with GPR174 loss-of-function variants.

Main Methods:

• Analysis of a cohort of six individuals with GPR174 variants.
• Histological examination of lymph nodes.
• Flow cytometry and gene expression profiling of patient T cells.
• Functional assays assessing T cell proliferation and cytokine production.
• Murine models of viral infection.

Main Results:

• Individuals with GPR174 variants presented with lymphadenopathy and autoimmunity, including Kikuchi-Fujimoto disease.
• GPR174 deficiency led to the overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (T_EMRA).
• GPR174-deficient T cells exhibited reduced suppression by lysophosphatidylserine (lysoPS) and an effector-biased gene expression profile, with impaired IL-2 suppression in CD4 T cells.
• GPR174-deficient mice showed over-accumulation of effector CD8 T cells during chronic viral infection.

Conclusions:

• GPR174 plays a critical role in regulating human T cell responses.
• Loss-of-function variants in GPR174 represent an inborn error of immunity, predisposing individuals to lymphoproliferation and autoimmunity, particularly after viral infections.
• GPR174 deficiency may be a genetic risk factor for conditions like Kikuchi-Fujimoto disease and other autoimmune disorders.