Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 191, Issue 12, Pages 2197-2207Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.191.12.2197
Keywords
immune deficiency; apoptosis; mitochondria; purine metabolism; T lymphocyte
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Funding
- NIDDK NIH HHS [DK-20902] Funding Source: Medline
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We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain insight into the mechanism of immune deficiency disease associated with PNP deficiency in humans. Similar to the human disease, PNP deficiency in mice causes an immunodeficiency that affects T lymphocytes more severely than B lymphocytes. PNP knockout mice exhibit impaired thymocyte differentiation, reduced mitogenic and allogeneic responses, and decreased numbers of maturing thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice exhibit increased apoptosis in vivo and higher sensitivity to gamma irradiation in vitro. We propose that the immune deficiency in PNP deficiency is a result of inhibition of mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.
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