Dysregulation of B7.2 (CD86) expression on monocytes of HIV-infected individuals is associated with altered production of IL-2

Abstract

SUMMARYT helper (Th) responses are mediated in part by immunoregulatory cytokines and the signals delivered by the costimulatory CD28-B7 pathway. In this study, we have investigated the relationship between the regulation of B7 isoform expression on antigen-presenting cells from HIV þ individuals and the production of Th cytokines. The level of expression of both B7.1 and B7.2 isoforms as measured by mean channel fluorescence was significantly decreased on freshly isolated monocytes from HIV þ individuals compared with HIV ¹ controls. However, the levels of expression of B7.1 and B7.2 on both B cells and monocytes increased significantly following culture in HIV þ individuals compared with HIV ¹ controls. B7 expression is subject to regulation by immunoregulatory cytokines. Therefore, we analysed the regulation of B7 expression by cytokines, namely IL-10 and tumour necrosis factor-alpha (TNF-a), the production of which is enhanced in HIV infection and have similar inhibitory effects on B7 expression. Two groups of HIV þ individuals were distinguished on the basis of the inhibitory effect of IL-10 and TNF-a on monocyte B7.2 expression. IL-10 inhibited B7.2 expression on monocytes from some HIV þ individuals (termed responders) like the HIV ¹ controls. However, in a subset of HIV þ individuals (non-responders) this inhibitory effect was lost. Loss of inhibition of B7.2 expression by IL-10 was associated with significantly reduced IL-2 production by phytohaemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMC). These observations showing an association of B7 dysregulation on monocytes and B cells with altered production of IL-2 may have implications in HIV immunopathogenesis.

Deleterious Effect of HIV-1 Plasma Viremia on B Cell Costimulatory Function

“…In this regard, CD28 has been shown to be critical in events that lead to migration of T cells to B cell areas (40). Finally, costimulatory pathways may offer potential therapeutic avenues, especially considering numerous other studies that have shown similar APC deficiencies with monocytes and dendritic cells of HIV-infected patients (23)(24)(25)(26)(27).…”

“…Dysregulation of CD80 and CD86 expression on Ag-presenting monocytes and dendritic cells has been described in HIV infection, with predicted deleterious consequences on Ag-responsive immune competent cells including T cell apoptosis (23), induction of premature B cell terminal differentiation (24), and loss of T cell responsiveness to antigenic stimulation (25)(26)(27). Furthermore, abnormal expression of CD80 and CD86 on T cells of HIV-infected patients has been described and thought to be associated with the Department of Health and Human Services, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 effects of HIV-induced immune activation (28), similar to what occurs in other inflammatory diseases (29,30).…”

Macrophages and HIV-1: dangerous liaisons

“…Monocyte/macrophage functions that are essential for adequate innate and adaptive responses to pathogens, such as antigen presentation, intracellular pathogen killing or phagocytosis, are affected by HIV-1 infection (Biggs et al, 1995;Kumar et al, 1999;Polyak et al, 1997;Yoo et al, 1996); revewed in (Kedzierska et al, 2003a). Phagocytosis is mediated by a number of phagocytic receptors expressed on monocytes/macrophages, including complement receptors (CR) and receptors for the Fc portion of immunoglobulins (FcR) (Aderem and Underhill, 1999) (Kedzierska et al, 2002).…”

Regulation of B7.1 Costimulatory Molecule Is Mediated by the IFN Regulatory Factor-7 through the Activation of JNK in Lipopolysaccharide-Stimulated Human Monocytic Cells

“…B7.1 expression was measured by flow cytometry as described previously (15,37). Briefly, cells were double stained with 3 l of FITC-labeled anti-CD14 mAb, and 3 l of PE-conjugated anti-B7.1 mAb (BD Pharmingen).…”