An autoimmune disease risk SNP, rs2281808, in SIRPG is associated with reduced expression of SIRP\u03b3 and heightened effector state in human CD8 T-cells

Sushmita Sinha,Michael P Crawford,Michael Tansey,John Kamholz,Nitin J Karandikar,Eva Tsalikian,Heena Olalde,Nicholas Borcherding,Pranav S Renavikar,Ezzatollah T Shivapour,Frank Bittner,Emilee Gibson

doi:10.1038/s41598-018-33901-1

Sushmita Sinha, Michael P Crawford + Show 10 more

Open Access

https://doi.org/10.1038/s41598-018-33901-1

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Journal: Scientific Reports	Publication Date: Oct 18, 2018
Citations: 13	License type: open-access

Affiliation: University of Iowa

Abstract

Multiple GWAS studies have shown that the SNP rs2281808 TT variant, present within the SIRPG gene, is associated with autoimmune diseases, such as type 1 diabetes. However, the role of SIRPγ in human T-cells is not known, neither is the functional significance of TT variant. Here we investigated SIRPG genotypes and their effects on the fate and function of human T-cells. We found that the presence of T variant resulted in reduction of SIRPγ expression on T-cells. Functionally, SIRPγlow CD8 T-cells in CT and TT individuals existed in a heightened effector state with lower activation threshold and had greater expression of genes and molecules associated with migratory and cytotoxic potential. Further, SIRPγlow CD8 T-cells were deficient in transcription factors associated with long-term functional memory formation. Our study reveals biological consequences of the SNP rs2281808 and provides novel insights into the potential mechanisms by which SIRPγ might regulate human immune responses.

Highlights

Genome-wide association studies have been instrumental in identifying genetic risk variants in autoimmune diseases
Multiple GWAS studies have identified rs2281808 TT variant as a genetic risk factor for type 1 diabetes (T1D), including a study that performed a meta-analysis on combined samples from UK and USA1
We have found a significantly higher preponderance of TT variant in T1D subjects as compared to healthy donors (HD vs. T1D, 4% vs. 22%; data not shown)

Summary

Introduction

Genome-wide association studies have been instrumental in identifying genetic risk variants in autoimmune diseases. We provide the first evidence that rs2281808 T variant is associated with a reduction in SIRPγ expression on human T-cells and that this can have potentially pathogenic consequences since SIRPγlow CD8 T-cells were characterized by exaggerated effector responses.

Results

Conclusion