1. ¹Monocyte Trafficking Unit, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
2. ²Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
3. ³Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

Correspondence: SH Jackson, Laboratory of Host Defenses, NIAID, NIH, CRC Building 5-West Labs, Room 5-3942, 10 Center Dr. MSC 1456, Bethesda, MD 20892-1456, USA. Tel: +301 435 8540; Fax: +301 480 3549; E-mail: sjackson@niaid.nih.gov

Received 17 June 2008; Revised 25 July 2008; Accepted 30 July 2008; Published online 19 September 2008.

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.