p47phox-deficient immune microenvironment signals dysregulate naive T-cell apoptosis.
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.
Donaldson
M
M
Monocyte Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-145, USA.
Antignani
A
A
Milner
J
J
Zhu
N
N
Wood
A
A
Cardwell-Miller
L
L
Changpriroa
C M
CM
Jackson
S H
SH
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D000072224:Bcl-2-Like Protein 11; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D005949:Glucose Oxidase; D006105:Granulomatous Disease, Chronic / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006861:Hydrogen Peroxide; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015851:Interleukin-7 / Q000276:immunology / Q000494:pharmacology; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051336:Mitochondrial Membranes / Q000201:enzymology / Q000276:immunology; D019255:NADPH Oxidases / Q000235:genetics / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000276:immunology
D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D015851:Interleukin-7; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1