Mitochondrial basis for immune deficiency: Evidence from purine nucleosidephosphorylase-deficient mice

We generated purine nucleoside phosphorylase (PNP)-deficient mice to gain i nsight 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 maturi ng thymocytes and peripheral T cells. T lymphocytes of PNP-deficient mice e xhibit increased apoptosis in vivo and higher sensitivity to gamma irradiat ion 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 cel ls to spontaneous mitochondrial DNA damage, leading to T cell depletion by apoptosis.