G307S DNAM-1 Mutation Exacerbates Autoimmune Encephalomyelitis via Enhancing CD4+ T Cell Activation
Rikito Murata1,2, Shota Kinoshita1,2, Kenshiro Matsuda1,3
1Department of Immunology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Abstract:
Although rs763361, which causes a nonsynonymous glycine-to-serine mutation at residue 307 (G307S mutation) of the DNAX accessory molecule-1 (DNAM-1) immunoreceptor, is a single-nucleotide polymorphism associated with autoimmune disease susceptibility, little is known about how the single-nucleotide polymorphism is involved in pathogenesis. In this study, we established human CD4+ T cell transfectants stably expressing wild-type (WT) or G307S DNAM-1 and showed that the costimulatory signal from G307S DNAM-1 induced greater proinflammatory cytokine production and cell proliferation than that from wild-type DNAM-1. The G307S mutation also enhanced the recruitment of the tyrosine kinase Lck and augmented p-Tyr322 of DNAM-1. We also established a mouse myelin Ag-specific CD4+ T cell transfectant stably expressing the chimeric DNAM-1 (chDNAM-1) consisting of the extracellular, transmembrane, and a part of intracellular regions of mouse DNAM-1 (residues 1-285) fused with the part of the intracellular region (residues 286-336) of human WT or G307S chDNAM-1. Adoptive transfer of the mouse T cell transfectant expressing the G307S chDNAM-1 into mice exacerbated experimental autoimmune encephalomyelitis compared with the transfer of cells expressing the WT chDNAM-1. These findings suggest that rs763361 is a gain-of-function mutation that enhances DNAM-1-mediated costimulatory signaling for proinflammatory responses.
Insights
The rs763361 single-nucleotide polymorphism enhances DNAX accessory molecule-1 (DNAM-1) signaling, increasing proinflammatory responses and autoimmune disease severity. This gain-of-function mutation in DNAM-1 promotes T cell activation and exacerbates experimental autoimmune encephalomyelitis.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- Autoimmune diseases are linked to the rs763361 single-nucleotide polymorphism (SNP).
- The rs763361 SNP results in a glycine-to-serine mutation at residue 307 (G307S) in the DNAX accessory molecule-1 (DNAM-1) immunoreceptor.
- The precise role of this SNP in autoimmune pathogenesis remains unclear.
Purpose of the Study:
- To investigate the functional impact of the G307S mutation on DNAM-1 signaling.
- To determine how this mutation contributes to autoimmune disease development.
Main Methods:
- Established human CD4+ T cell transfectants expressing wild-type (WT) or G307S DNAM-1.
- Created chimeric DNAM-1 (chDNAM-1) constructs for mouse models.
- Utilized adoptive transfer of engineered T cells into mice to assess disease exacerbation.
Main Results:
- G307S DNAM-1 signaling induced greater proinflammatory cytokine production and T cell proliferation compared to WT DNAM-1.
- The G307S mutation enhanced Lck recruitment and DNAM-1 phosphorylation at Tyr322.
- Transfer of mouse T cells expressing G307S chDNAM-1 worsened experimental autoimmune encephalomyelitis (EAE) in mice.
Conclusions:
- The rs763361 SNP represents a gain-of-function mutation in DNAM-1.
- Enhanced DNAM-1 costimulatory signaling by the G307S mutation promotes proinflammatory responses.
- This mutation contributes to autoimmune pathogenesis, as evidenced by exacerbated EAE.
