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A single-nucleotide polymorphism in the human ENTPD1 gene encoding CD39 is associated with worsened graft-versus-host disease in a humanized mouse model
- Source :
- Immunology and cell biologyREFERENCES. 98(5)
- Publication Year :
- 2019
-
Abstract
- Regulatory T cells (Tregs) protect against graft-versus-host disease (GVHD), a life-threatening complication of allogeneic hematopoietic stem cell transplantation. The ectoenzyme CD39 is important for increasing the immunosuppressive function of Tregs. The rs10748643 (A → G) single-nucleotide polymorphism (SNP) in intron 1 of the human ENTPD1 gene is associated with increased proportions of CD39+ Tregs. This study aimed to determine whether the rs10748643 SNP corresponded to increased proportions of CD39+ Tregs in an Australian donor population, and whether this SNP influences clinical GVHD in a humanized mouse model. Donors were genotyped for the rs10748643 SNP by Sanger sequencing, and the proportion of CD39+ T cells in donor peripheral blood was determined by flow cytometry. Donors encoding the G allele (donorsAG/GG ) demonstrated higher proportions of CD39+ CD3+ CD4+ CD25+ CD127lo Tregs, but not CD39+ CD3+ CD8+ T cells or CD39+ CD3+ CD4+ conventional T cells, compared with donors homozygous for the A allele (donorsAA ). NOD-SCID-IL2Rγnull mice were injected with human peripheral blood mononuclear cells from either donorsAA (hCD39AA mice) or donorsAG/GG (hCD39AG/GG mice). hCD39AG/GG mice demonstrated significantly greater weight loss and GVHD clinical scores, and significantly reduced survival, compared with hCD39AA mice. hCD39AG/GG mice showed significantly higher hCD4+ :hCD8+ T-cell ratios than hCD39AA mice, but displayed similar proportions of CD3+ hCD4+ hCD25+ hCD127lo Tregs and hCD39+ Tregs. However, the proportion of human Tregs corresponded to survival in hCD39AA mice, but not in hCD39AG/GG mice. This study demonstrates that donors encoding the G allele show higher percentages of CD39+ Tregs, but cause worsened GVHD in humanized mice compared with donors homozygous for the A allele.
- Subjects :
- medicine.medical_treatment
Immunology
Population
Graft vs Host Disease
chemical and pharmacologic phenomena
Single-nucleotide polymorphism
Hematopoietic stem cell transplantation
Mice, SCID
Biology
Peripheral blood mononuclear cell
Polymorphism, Single Nucleotide
T-Lymphocytes, Regulatory
Mice
Mice, Inbred NOD
medicine
Immunology and Allergy
Animals
Humans
IL-2 receptor
education
education.field_of_study
Apyrase
Australia
Cell Biology
medicine.disease
Graft-versus-host disease
Humanized mouse
Leukocytes, Mononuclear
CD8
Subjects
Details
- ISSN :
- 14401711
- Volume :
- 98
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Immunology and cell biologyREFERENCES
- Accession number :
- edsair.doi.dedup.....c0c579073a65dc733393ccb80939000f