Abstract
The risk for non-Hodgkin lymphoma (NHL) is markedly increased in persons living with human immunodeficiency virus (HIV) infection, and remains elevated in those on anti-retroviral therapy (cART). Both the loss of immunoregulation of Epstein-Barr virus (EBV) infected cells, as well as chronic B-cell activation, are believed to contribute to the genesis of AIDS-related NHL (AIDS-NHL). However, the mechanisms that lead to AIDS-NHL have not been completely defined. A subset of B cells that is characterized by the secretion of IL10, as well as the expression of the programmed cell death ligand-1 (PD-L1/CD274), was recently described. These PD-L1+ B cells can exert regulatory function, including the dampening of T-cell activation, by interacting with the program cell death protein (PD1) on target cells. The role of PD-L1+ B cells in the development of AIDS-NHL has not been explored. We assessed B cell PD-L1 expression on B cells preceding AIDS-NHL diagnosis in a nested case-control study of HIV+ subjects who went on to develop AIDS-NHL, as well as HIV+ subjects who did not, using multi-color flow cytometry. Archival frozen viable PBMC were obtained from the UCLA Multicenter AIDS Cohort Study (MACS). It was seen that the number of CD19+CD24++CD38++and CD19+PD-L1+cells was significantly elevated in cases 1–4 years prior to AIDS-NHL diagnosis, compared to controls, raising the possibility that these cells may play a role in the etiology of AIDS-NHL. Interestingly, most PD-L1+ expression on CD19+ cells was seen on CD19+CD24++CD38++ cells. In addition, we showed that HIV can directly induce PD-L1 expression on B cells through interaction of virion-associated CD40L with CD40 on B cells.
Highlights
The risk for non-Hodgkin lymphoma (NHL) is markedly increased in persons living with human immunodeficiency virus (HIV) infection, and remains elevated in those on anti-retroviral therapy
We show that numbers of both Breg cells (CD19+CD24++CD38++ cells) and CD19+PD-L1+ cells were elevated in the peripheral circulation of HIV+ subjects prior to AIDS-NHL diagnosis, when compared to the levels seen in HIV+ controls who did not develop AIDS-NHL
We show that Breg cells (CD19+CD24++CD38++), as well as B cells expressing PD-L1 (CD19+PD-L1+ cells), are elevated prior to AIDS-NHL diagnosis
Summary
The risk for non-Hodgkin lymphoma (NHL) is markedly increased in persons living with human immunodeficiency virus (HIV) infection, and remains elevated in those on anti-retroviral therapy (cART) Both the loss of immunoregulation of Epstein-Barr virus (EBV) infected cells, as well as chronic B-cell activation, are believed to contribute to the genesis of AIDS-related NHL (AIDS-NHL). We and others have shown that HIV virions can directly activate B cells and induce AICDA expression, via host cell-produced stimulatory molecules that are incorporated into HIV, such as CD40 ligand (CD40L)[23,24]. These studies provide strong evidence that B cell activation precedes and may contribute to the development of AIDS-NHL. This Breg population can dampen T cell function, mainly by producing and secreting IL10 and TGFβ, in a manner analogous to that of Treg cells[25]
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