Immune Suppression by Neutrophils in HIV-1 Infection: Role of PD-L1/PD-1 Pathway

Abstract

HIV-1 infection is associated with a progressive loss of T cell functional capacity and reduced responsiveness to antigenic stimuli. The mechanisms underlying T cell dysfunction in HIV-1/AIDS are not completely understood. Multiple studies have shown that binding of program death ligand 1 (PD-L1) on the surface of monocytes and dendritic cells to PD-1 on T cells negatively regulates T cell function. Here we show that neutrophils in the blood of HIV-1-infected individuals express high levels of PD-L1. PD-L1 is induced by HIV-1 virions, TLR-7/8 ligand, bacterial lipopolysaccharide (LPS), and IFNα. Neutrophil PD-L1 levels correlate with the expression of PD-1 and CD57 on CD4+ and CD8+ T cells, elevated levels of neutrophil degranulation markers in plasma, and increased frequency of low density neutrophils (LDNs) expressing the phenotype of granulocytic myeloid-derived suppressor cells (G-MDSCs). Neutrophils purified from the blood of HIV-1-infected patients suppress T cell function via several mechanisms including PD-L1/PD-1 interaction and production of reactive oxygen species (ROS). Collectively, the accumulated data suggest that chronic HIV-1 infection results in an induction of immunosuppressive activity of neutrophils characterized by high expression of PD-L1 and an inhibitory effect on T cell function.

Programmed Death Ligand 1 on Burkholderia pseudomallei–Infected Human Polymorphonuclear Neutrophils Impairs T Cell Functions

“…The rapidity of the response suggests that PD-L1 is directly induced by the pathogen, consistent with previous reports in which inactivated HIV-1 virions directly upregulate neutrophil PD-L1 expression (21). Macrophages, dendritic cells, and neutrophils can be induced to express PD-L1 after engagement of TLR ligands LPS and R848 to their receptors TLR4 and TLR8 (21). PD-L1 upregulation on B. pseudomallei-infected PMNs might be explained by B. pseudomallei expressing LPS that signals through TLRs (34).…”

“…However, our findings of reduced T cell responses mediated by PD-L1 on B. pseudomalleiinfected PMNs are consistent with the increasing involvement of this pathway in regulating antimicrobial responses to acute infections (24,37). This is strongly supported by a report demonstrating that IFN-g-stimulated neutrophils after acute inflammatory responses suppress T cell function via their expression of PD-L1 on neutrophils (21). In other systems, the key role of PD-1/PD-L1 pathway in T cell suppression has led to development of strategies to manipulate the interaction of PD-1 and PD-L1 for the reversal of exhausted T cells and improvement of pathogen control.…”

“…The mechanism(s) leading to the upregulation of PD-L1 in B. pseudomallei infection is likely mediated by a combined effect of several factors. The rapidity of the response suggests that PD-L1 is directly induced by the pathogen, consistent with previous reports in which inactivated HIV-1 virions directly upregulate neutrophil PD-L1 expression (21). Macrophages, dendritic cells, and neutrophils can be induced to express PD-L1 after engagement of TLR ligands LPS and R848 to their receptors TLR4 and TLR8 (21).…”

“…However, there is increasing interest in the potential immunosuppressive activity of human PMNs on cells of the adaptive immune response (7,8,21). In this study, we demonstrated that the interaction of uninfected PMNs and, to a greater extent, B. pseudomallei-infected PMNs and T cells results in potent inhibition of T cell proliferation and cytokine production, adding new information on the immunoregulatory properties of neutrophils in the context of acute bacterial infection.…”

“…In tuberculosis, the PD-1/PD-L1 pathway suppresses Mycobacterium tuberculosis-specific IFN-g production and cytotoxicity by T cells from TB patients (18). In HIV-1 infection, there is evidence that this pathway also suppresses IFN-g production by T cells from HIV patients (21). Some studies have suggested a pathological role for PD-1/PD-L1 by reducing microbial clearance and innate inflammatory responses, but accelerating T cell apoptosis in sepsis (22)(23)(24).…”