Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function
Huang, Y.-H.; Arana, K.; Rachimi, S.; Tam, H.; Spegarova, J. S.; Engelhardt, K. R.; Griffin, H.; Mee, M.; Miano, M.; Raggi, F.; Grossi, A.; Rusmini, M.; Ceccherini, I.; Dell'Orso, G.; Ferro, J.; Giarratana, M. C.; Pillai, V.; Banka, S.; Garcez, T.; Briggs, T. A.; Mellouli, F.; von Hardenberg, S.; Beier, R.; Auber, B.; Baumann, U.; Tawamie, H.; Behrens, E.; Oldridge, D. A.; Cabrera, E. C.; Xu, Y.; Ouyang, S.; Hambleton, S.; Romberg, N.; Cyster, J. G.
Show abstract
The X-linked G-protein coupled receptor GPR174 is highly expressed in T and B lymphocytes and has immunoregulatory roles in mice, but its function in humans is unknown. We describe a cohort of six individuals who have function-disrupting variants in GPR174 and a clinical phenotype of lymphadenopathy and autoimmunity. Histological analysis of two patient lymph nodes revealed necrotizing lymphadenitis and lymphoproliferation resembling Kikuchi-Fujimoto disease. In-depth analysis of three patients and related carriers revealed overaccumulation of CD8 terminally differentiated effector memory cells re-expressing CD45RA (TEMRA). Patient cells and GPR174-deficient CD8 T cells generated from controls showed less repression of proliferation by the GPR174 ligand lysophosphatidylserine (lysoPS) and an effector-biased gene expression program. GPR174-deficient CD4 T cells were resistant to lysoPS-mediated suppression of IL2 production. In mice, chronic viral infection led to over-accumulation of GPR174-deficient effector CD8 T cells. We describe an inborn error of immunity associated with dysregulated lymphocyte responses that we propose predisposes to exaggerated lymphoproliferation and autoimmunity following viral infection.
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