HIV infection is associated with a greatly increased risk for non-Hodgkin lymphoma (NHL). Nearly all AIDS- related lymphomas (ARL) are of B cell origin. A population of B cells with regulatory function, which have been termed ?regulatory B cells? (Bregs), has been recently recognized. Bregs are analogous to regulatory T cells, or Tregs, which are T cells that can dampen adaptive immune responses via the secretion of inhibitory cytokines, such as IL10 and TGF-?. It was recently shown that plasmacytoid dendritic cells (pDC) control the differentiation of immature B cells into CD24+CD38+ Breg cells or plasmablasts, and that pDC-induced CD24+CD38+ Breg cells might reciprocally regulate pDC-derived IFN? production. We have recently shown that Bregs are elevated 1-4 years prior to ARL, and that these Breg cells express PDL1. PDL1 is an immune inhibitory receptor that binds to PD1 (mainly in T cells) to dampen immune response. Therefore, Breg cells present prior to ARL may contribute to lymphomagenesis in a dual fashion, by: 1) enhancing B cell activation, and 2) by impairing/inhibiting T cell function, including cytotoxic T cells (CTL) involved in the immunoregulation of Epstein-Barr virus (EBV) infected B cells and/or HIV-infected CD4 T cells. For this reason, it is important to study how these cells arise during lymphomagenesis. Here we propose to study whether pDC, which are activated in HIV infection, are contributing to the elevation of PDL1+ Breg cells observed 1-4 years prior to ARL diagnosis. Additionally, it was recently shown that ARL tumor cells express PDL1+. Because of this, we propose to determine if the PDL1+ Breg cells seen prior to ARL display characteristic molecular changes that are seen in ARL, and also, if these cells contain the B cell clone from which ARL emerges, and are, therefore, pre-tumor cells.
B cell dysfunction, including chronic B cell hyperactivation, is commonly seen in HIV-infected persons, and is only partially corrected by antiretroviral therapy (cART). The studies outlined in this proposal aim to delineate the mechanisms by which PDL1+ Breg cells arise prior to AIDS-related lymphoma (ARL), and to determine if they are pre-tumor cells. The results of these studies will provide valuable new insights relevant to the development of ARL, will provide new therapeutic targets, and will inform the development of new treatments to prevent ARL.