[HTML][HTML] p47phox-deficient immune microenvironment signals dysregulate naive T-cell apoptosis

M Donaldson, A Antignani, J Milner, N Zhu… - Cell Death & …, 2009 - nature.com
M Donaldson, A Antignani, J Milner, N Zhu, A Wood, L Cardwell-Miller, CM Changpriroa…
Cell Death & Differentiation, 2009nature.com
The phagocyte NADPH oxidase is a multicomponent enzyme complex mediating microbial
killing. We find that NADPH oxidase p47 phox-deficient (p47 phox−/−) chronic
granulomatous disease (CGD) mice develop lymph node hyperplasia even without obvious
infection, where increased number of T and B lymphocytes is associated with increased
percent of naïve cells and a lower T: B cell ratio than wild type. Paradoxically, despite
lymphoid hyperplasia in vivo, when lymphocytes are placed in culture, p47 phox−/− CD8+ …
Abstract
The phagocyte NADPH oxidase is a multicomponent enzyme complex mediating microbial killing. We find that NADPH oxidase p47 phox-deficient (p47 phox−/−) chronic granulomatous disease (CGD) mice develop lymph node hyperplasia even without obvious infection, where increased number of T and B lymphocytes is associated with increased percent of naïve cells and a lower T: B cell ratio than wild type. Paradoxically, despite lymphoid hyperplasia in vivo, when lymphocytes are placed in culture, p47 phox−/− CD8+ lymphocytes progress more rapidly to apoptosis than wild type. This is associated in cultured p47 phox−/− CD8+ lymphocytes with the induction of proapoptotic Bim and Puma expression, increased mitochondrial outer membrane permeabilization and depressed Bcl-2 expression. Addition of IL-7 to the culture partially corrects Bcl-2 levels in cultured p47 phox−/− CD8+ lymphocytes and improves the survival. Adding glucose oxidase to the culture to generate hydrogen peroxide along with IL-7 further improves p47 phox−/− CD8+ lymphocyte survival, but only to 30% of wild type. We conclude that p47 phox−/− CD8+ lymphocytes have an intrinsic survival defect likely in part related to the oxidase deficiency, but in vivo in lymph nodes of CGD mice, there are microenvironmental factors yet to be delineated that suppress the progression of apoptosis and allow the accumulation of lymphocytes leading to lymphoid hyperplasia.
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