Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+ T cell function in vitro

Abstract

HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL-10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression.

Human regulatory B cells in health and disease: therapeutic potential

“…In the same paper, Bregs were shown to suppress HIV-1-specific CD8 + T cell responses in an IL-10-and PD-L1-dependent manner (59). The suppressive role of Bregs during HIV infection was confirmed by depletion of Bregs from peripheral blood mononuclear cells (PBMCs) in vitro, which resulted in restored CD8…”

“…+ T cell effector function as well as clearance of infected CD4 + T cells (59). Similarly, the frequency of another subset of IL-10-producing Bregs with a CD19 + TIM1…”

Upregulation of CD19+CD24hiCD38hi regulatory B cells is associated with a reduced risk of acute lung injury in elderly pneumonia patients

“…CD24 hi CD38 hi B cells and suppression of T cell inflammation contributed to the development and persistence of microbial pneumonia. In HIV infection, induction of IL-10 by B cells during acute/ early HIV infection was suggested to act as a viral evasion strategy [25,26]. More studies are needed to examine the contribution of CD19 ?…”

Exploitation of Interleukin-10 (IL-10) Signaling Pathways: Alternate Roles of Viral and Cellular IL-10 in Rhesus Cytomegalovirus Infection

“…One striking finding of this study is that there are significant correlations between the levels of antigenstimulated cIL-10 production in PBMC and RhCMV genome copy numbers detected in saliva. This is not unique to RhCMV, as cIL-10 levels have been positively associated, either alone or with other biomarkers, with increased burdens of other pathogens, including human papillomavirus, HIV, hepatitis B virus, EpsteinBarr virus (EBV), Mycobacterium tuberculosis, Leishmania spp., dengue virus, and murine and human CMV (45,(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72). While the specific cell type(s) responsible for elevated cIL-10 expression in response to RhCMV antigen exposure was not explored, multiple cell types have been implicated for other pathogens, including regulatory B and T cells.…”