Effects of purine nucleoside phosphorylase deficiency on thymocyte development.
J Allergy Clin Immunol
; 128(4): 854-863.e1, 2011 Oct.
Article
en En
| MEDLINE
| ID: mdl-21868080
ABSTRACT
BACKGROUND:
Inherited or acquired defects in purine nucleoside phosphorylase (PNP) impair purine metabolism, as well as the survival and function of T lymphocytes. However, the effects of PNP deficiency on thymocyte development are not well known.OBJECTIVES:
We sought to study thymocyte development in PNP-deficient (PNP-KO) mice.METHODS:
Maturation, proliferation, and apoptosis were determined in thymocytes from PNP-KO mice and hematopoietic stem cells from these mice grown ex vivo into thymocyte-like cells.RESULTS:
Reduced percentages of CD4(+)CD8(+) double-positive (DP) thymocytes with normal percentages of CD4(-)CD8(+) and CD4(+)CD8(-) single-positive thymocytes were found in the thymi of PNP-KO mice. Similarly, reduced DP-like thymocytes grew ex vivo from hematopoietic stem cells of PNP-KO mice. Thymi of PNP-KO mice contained increased apoptotic DP thymocytes. Increased apoptosis of PNP-deficient DP thymocytes occurred after exposure to deoxyguanosine (dGuo), although not after Fas ligation, and could be prevented by restoring PNP activity within the cells. In DP thymocytes from PNP-KO mice, dGuo caused mitochondrial membrane potential dissipation and induced release of cytochrome c from the mitochondria followed by nuclear DNA fragmentation. Inhibition of the caspase pathway prevented dGuo-induced nuclear DNA fragmentation but not mitochondrial membrane potential dissipation, indicating that PNP deficiency induces apoptosis that is initiated in the mitochondria of DP thymocytes. 5-Bromo-2-deoxyuridine incorporation demonstrated that PNP deficiency does not interfere with DP or single-positive thymocyte proliferation.CONCLUSIONS:
PNP is important for the survival of DP thymocytes. Accumulation of dGuo in cases of PNP deficiency leads to mitochondria-initiated apoptosis of DP thymocytes, which can be prevented by restoring PNP activity in the cells.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Timo
/
Linfocitos T
/
Purina-Nucleósido Fosforilasa
/
Apoptosis
/
Proliferación Celular
Límite:
Animals
Idioma:
En
Revista:
J Allergy Clin Immunol
Año:
2011
Tipo del documento:
Article
País de afiliación:
Canadá