B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression

Abstract

The ligation of programmed death-ligand 1 (B7-H1) to T cells results in the preferential production of interleukin 10 (IL-10). We investigated if B7-H1 would be upregulated in HIV infection, a disease characterized by increased IL-10 production, by measuring B7-H1, B7-1 (CD80), and B7-2 (CD86) expression and mRNA in 36 HIV-infected patients and in 22 healthy controls (HCs). Results showed that (1) B7-H1 expression and mRNA are augmented in cells of HIV patients; (2) increased IL-10 production in these patients is largely induced by B7-H1-expressing CD14 ؉ cells; (3) an inverse correlation is detected between B7-H1 expression and CD4 counts, whereas the up-regulation of B7-H1 is directly associated with HIV plasma viremia; (4) antiviral therapy results in the parallel down modulation of IL-10 production and B7-H1 expression/ synthesis; and ( IntroductionThe activation of T lymphocytes is dependent on the presentation of processed antigenic peptides in association with major histocompatibility (MHC) molecules to lymphocytes that express a T-cell receptor specific for that binary complex. 1,2 However, optimal lymphocyte activation requires a second signal that is delivered by the interaction between costimulatory, accessory molecules. 3,4 The cross-linking of CD28 on the surface of T lymphocytes allows for the activation of these cells. CD28 binds to a family of ligands on the surface of non-T cells that are collectively known as B7 molecules. 5,6 Beside B7.1 (CD80) and B7.2 (CD86), a number of other B7-like ligands have been described. 7-9 Among these ligands, B7-H1 is particularly interesting. B7-H1, also called PD-L1, is constitutively present on monocytes and could be induced on activated T cells. 7 B7-H1 does not interact with CD28, cytotoxic T-lymphocyte antigen 4 (CTLA-4), or inducible costimulator (ICOS) but was shown to bind to programmed death 1 (PD-1) 10,11 a CTLA-4-like molecule belonging to the immunoglobulin superfamily. Studies, however, suggested that receptors other than PD-1 can also ligate B7-H1. 7 Ligation of B7-H1 to T cells results in the preferential production of interleukin-10 (IL-10) 7 and in increased T-helper-dependent synthesis of trinitrophenyl (TNP)-specific immunoglobulin G2a (IgG2a) 12 in mice. These results suggest that ligation of B7-H1 may be responsible for promoting type 2 cytokine-biased responses.Interleukin-10 production by peripheral blood mononuclear cells (PBMCs) is augmented in infectious and noninfectious pathologies, including HIV disease. [13][14][15][16] In particular, cell-mediated immunity (CMI) is characteristically impaired in HIV infection. [17][18][19][20] The progression of this infection is associated with increased HIV replication, reduction of circulating CD4 ϩ T lymphocytes, functional defects of CMI, and augmented apoptosis of T lymphocytes. 21,22 An impairment in the production of type 1 cytokines accompanied by increased secretion of type 2 cytokines has also repeatedly been suggested to accompany progression of HIV disease. 14,16,23,24 Because IL-10, ...

ERK/p38 MAP‐kinases and PI3K are involved in the differential regulation of B7‐H1 expression in DC subsets

“…Although freshly isolated blood DC express only low levels of B7-H1, they upregulate the expression of this molecule once matured by cytokines and/or the TLR ligands poly I:C and LPS. That TLR triggering is indeed able to regulate B7-H1 expression in vivo has been suggested by studies showing upregulation of B7-H1 expression in mDC derived from HIV-and hepatitis-B-infected individuals [7,37].We further show that mDC can upregulate surface expression of B7-H1 directly in response to cytokines, poly I:C, LPS, whereas pDC only react to CpG with B7-H1 upregulation. The level of B7-H1 expression induced by maturation was significantly stronger in mDC as compared to pDC.…”

“…Although freshly isolated blood DC express only low levels of B7-H1, they upregulate the expression of this molecule once matured by cytokines and/or the TLR ligands poly I:C and LPS. That TLR triggering is indeed able to regulate B7-H1 expression in vivo has been suggested by studies showing upregulation of B7-H1 expression in mDC derived from HIV-and hepatitis-B-infected individuals [7,37].…”

B7-H1 Up-Regulation on Myeloid Dendritic Cells Significantly Suppresses T Cell Immune Function in Patients with Chronic Hepatitis B

“…This recovery was closely associated with increased IL-12 and decreased IL-10 secretion in the coculture supernatant. Together with other recent studies of HIV-1 (30) and HBV (35) infection in humans, this report suggested that up-regulation of B7-H1 on mDCs may lead to increased inhibitory signals mediated by B7-H1 and its receptors, thus promoting T cell functional deficiency in chronic HBV infection and perhaps subsequently facilitating viral persistence. In this study, a significant, positive correlation between B7-H1 expression on mDCs and plasma HBV DNA also supported this finding, although the cause-to-effect relationship between B7-H1 expression and viral replication needs future longitudinal investigation.…”

Costimulatory Pathways in Multiple Sclerosis: Distinctive Expression of PD-1 and PD-L1 in Patients with Different Patterns of Disease

“…This is achieved through two major and complementary mechanisms: the generation of IL-10, a powerful inflammation-dampening cytokine; and the limitation of the proliferation of Ag-specific cells, possibly via the triggering of apoptosis of such cells. In fact, PD-1 is abundantly expressed in diseases associated with increased IL-10 generation such as lung, ovary, and colon carcinoma (32,33) and HIV infection (34,35). In contrast, PD-1/ PD-L1 interactions modulate positive and negative selection in the thymus (36,37) and protect immune privileged sites such as the placenta (38,39) and the eye from immune responses (40,41).…”