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

Sci Rep. 2018 Oct 18;8(1):15440. doi: 10.1038/s41598-018-33901-1.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Antigens, Differentiation / biosynthesis
  • Antigens, Differentiation / genetics*
  • Antigens, Differentiation / physiology
  • Autoimmunity / genetics
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cytotoxicity, Immunologic
  • Female
  • Gene Expression Regulation
  • Genotype
  • Humans
  • Immunologic Memory / genetics
  • Lymphocyte Activation
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • Receptors, Immunologic / biosynthesis
  • Receptors, Immunologic / genetics*
  • Receptors, Immunologic / physiology
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism*

Substances

  • Antigens, Differentiation
  • Receptors, Immunologic
  • SIRPG protein, human