A role for NADPH oxidase in antigen presentation

Abstract

The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase expressed in phagocytes is a multi-subunit enzyme complex that generates superoxide (O2 (.-)). This radical is an important precursor of hydrogen peroxide (H2O2) and other reactive oxygen species needed for microbicidal activity during innate immune responses. Inherited defects in NADPH oxidase give rise to chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent infections and granulomatous inflammation. Interestingly, CGD, CGD carrier status, and oxidase gene polymorphisms have all been associated with autoinflammatory and autoimmune disorders, suggesting a potential role for NADPH oxidase in regulating adaptive immune responses. Here, NADPH oxidase function in antigen processing and presentation is reviewed. NADPH oxidase influences dendritic cell (DC) crosspresentation by major histocompatibility complex class I molecules through regulation of the phagosomal microenvironment, while in B lymphocytes, NADPH oxidase alters epitope selection by major histocompatibility complex class II molecules.

Keywords: B lymphocytes; NADPH oxidase; antigen presentation; autoimmunity; chronic granulomatous disease.

Figure 1

NADPH oxidase structure. NADPH oxidase is a multi-subunit enzyme complex present in the vesicular and plasma membranes of leukocytes. Two transmembrane subunits, gp91^phox and p22^phox, make up flavocytochrome b₅₅₈, the catalytic core of the complex. This heterodimer catalyzes the transfer of electrons from cytosolic NADPH to molecular oxygen, thus generating superoxide. Flavocytochrome b₅₅₈ is regulated by association with the subunits p47^phox, p67^phox, and p40^phox along with the small GTPase Rac. These regulatory subunits are present in the cytosol of resting cells and translocate to the catalytic core following stimulation.

Figure 2

Potential roles of NADPH oxidase in antigen presentation. MHC-I and MHC-II are both present in phagosomes and endosomes of antigen presenting cells. For simplicity, MHC-I has been shown in a phagosome, while MHC-II has been shown in an endosome. During crosspresentation, exogenous antigens can be processed within these compartments by proteases, prior to loading onto MHC-I. NADPH oxidase has been shown to regulate antigen processing and MHC-I crosspresentation in DC; however, whether NADPH oxidase regulates this process by modulating the phagosomal pH or redox microenvironment is currently debated. During classical MHC-II presentation, exogenous antigens are processed within vesicular compartments by proteases and GILT. Following the removal of CLIP by HLA-DM, processed peptides are loaded onto MHC-II. NADPH oxidase can also regulate MHC-II presentation in B cells by altering the peptide repertoire displayed by MHC-II, possibly in favor of self antigens. However, the mechanism underlying this phenomenon is still unclear. Whether or not NADPH oxidase, MHC-I and -II, and the antigen processing machinery co-localize within the same vesicular compartment also remains to be elucidated.