According to researchers, HIV virions expressing the ligand of CD40 (ie, CD40L) on their surface may drive lymphomagenesis in HIV-infected individuals by inducing expression of the programmed cell death-ligand 1 (PD-L1) on regulatory B cells (ie, Breg cells). The findings from this study were published in Scientific Reports.
Previous research has revealed the existence of a population of regulatory B cells (ie, Breg cells characterized by expression of CD19 (+), CD24 (++), and CD38 (++) which partially function in a manner analogous to regulatory T cells (ie, Treg cells) that secrete inhibitory cytokines (eg, interleukin-10 [IL-10]) to suppress the response of the adaptive immune system. Results of recent studies have shown high levels of IL-10-secreting B cells in HIV-positive individuals, and support promotion of Breg cell generation through HIV infection.
Individuals infected with HIV are known to be at increased risk of non-Hodgkin lymphoma (ie, AIDS-NHL), and previous work has implicated chronic B cell activation, as well as immune dysregulation due to B-cell infection with Epstein-Barr virus (EBV), as potential etiologic factors contributing to the development of AIDS-NHL. Furthermore, results from a recently conducted small study showed that the population of Breg cells was elevated in individuals infected with HIV diagnosed with AIDS-NHL compared with HIV-positive individuals without an AIDS-NHL diagnosis. In addition, previous research has demonstrated that Breg cells in HIV-infected individuals can express PD-L1.
In this nested case-control study conducted within the Multicenter AIDS cohort study, frozen samples of peripheral blood mononuclear cells (PBMC) from men with AIDS-NHL (n=18) collected greater than 4 years and 1-4 years prior to AIDS-NHL diagnosis were obtained. Similar specimens were also obtained from HIV-positive men without a diagnosis of AIDS-NHL (n=18). In addition, PBMC samples were collected from HIV-negative men (n=15). Multicolor flow cytometry was performed on stained PBMC to characterize biomarker expression and quantify cell populations.
Interestingly, the level of Breg cells (ie, CD19+CD24++CD38++ cells) was significantly elevated 1-4 years (P =.003), but not greater than 4 years, prior to diagnosis of AIDS-NHL compared with the HIV-positive control group who did not develop AIDS-NHL. The timing of the increase in Breg cells suggests that these cells may play a role in the generation of AIDS-NHL. In addition, the number of Breg cells was higher in PBMC samples of HIV-positive compared with HIV-negative individuals (P =.025).
Also observed was a significant increase in the level of B cells staining for both CD19 and PD-L1 1-4 years (P =.029), but not greater than 4 years, preceding the diagnosis of AIDS-NHL compared with PCMC samples from HIV-positive controls. Interestingly, most of these B cells also stained for the Breg phenotype, suggesting that a subpopulation of Breg cells expressing PD-L1 is associated with the development of AIDS-NHL.
Furthermore, PD-L1 expression on B cells was significantly higher in HIV-positive compared with HIV-negative individuals (P =.005 and P =.01 in individuals with and without a diagnosis of AIDS-NHL, respectively), suggesting that HIV infection is associated with increased B cell expression of PD-L1.
Additional experiments were designed to uncover the underlying mechanisms associated with upregulation of PD-L1 on B cells. Previous research showed HIV virions produced in human T cells express CD40L on their surface. The CD40 ligand (CD40L) is known to activate CD40, and CD40/CD40L signaling is necessary for Breg development/function. In this study, an increased level of PD-L1 expression was observed on isolated B cell samples from HIV-negative individuals exposed to HIV virions expressing CD40L (P =.032). However, when B cells were exposed to HIV virions positive for a mutant, nonfunctional form of CD40L, no increase in PD-L1 expression level was observed. In addition, B cells exposed to the CD40L-positive HIV virions were shown to secrete IL-10.
These results suggest that Breg cells may inhibit T cell function by secretion of IL-10 and through blockage of the costimulatory PD-1 receptor.
In their concluding remarks, the study authors noted that “together, these findings lead us to speculate that the induction of PD-L1 on B cells may be an early event driving lymphomagenesis. Certainly, more work needs to be done to elucidate the role of PD-L1-positive B cells in lymphomagenesis.”
Epeldegui M, Conti DV, Guo Y, et al. Elevated numbers of PD-L1 expressing B cells are associated with the development of AIDS-NHL. doi: 10.1038/s41598-019-45479-3