Background and Aims

Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling and has important functions in immune regulation acting on multiple intracellular pathways. Animal models predict autoimmunity dominated phenotypes and early death in complete knockout of SOCS1. Recently SOCS1 haploinsufficiency has been associated with novel Inborn error of immunity (IEI) in humans. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has pleiotropic effects in humans.

We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency.

Methods

We assessed impacts of reduced SOCS1 expression across immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells.

Results

SOCS1 haploinsufficiency phenotypes straddle across classifications of IEI. Reduced SOCS1 expression leads to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. These findings might explain clinical overlaps between SOCS1 haploinsufficiency and IEIs like STAT1GOF and STAT3LOF. Immune dysregulation in SOCS1 haploinsufficiency might further be explained by reduced E3 ligase functions of SOCS1 leading to increased FAK in immune cells resulting in increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also find Toll-like receptor responses being increased in SOCS1 patients.

Conclusions

SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain variable clinical phenotypes associated with this new condition. Knowledge of additional dysregulated pathways is important when considering specific treatment options for these patients.