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 function in human immunity remains largely uncharacterized.

Purpose of the Study:

• To investigate the role of GPR174 in human immune responses.
• To identify the clinical and cellular consequences of GPR174 loss-of-function variants.

Main Methods:

• Analysis of a cohort of six individuals with GPR174 function-disrupting 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.
• In vivo studies in a mouse model of viral infection.

Main Results:

• Individuals with GPR174 variants presented with lymphadenopathy and autoimmunity, including Kikuchi-Fujimoto disease.
• Patients exhibited an overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (T_EMRA).
• GPR174-deficient T cells showed reduced suppression of proliferation by lysophosphatidylserine (lysoPS) and an effector-biased gene expression profile.
• GPR174 deficiency rendered CD4 T cells resistant to lysoPS-mediated IL-2 suppression.
• GPR174-deficient mice infected with viruses showed increased effector CD8 T cell accumulation.

Conclusions:

• GPR174 loss-of-function represents an inborn error of immunity.
• Dysregulated lymphocyte responses, particularly in T cells, contribute to lymphoproliferation and autoimmunity.
• GPR174 deficiency may predispose individuals to exaggerated immune responses following viral infections.