HIV infection is associated with a greatly increased risk for the development of non-Hodgkin lymphoma (NHL). Nearly all AIDS-related lymphomas (ARL) are of B cell origin. Two major mechanisms are believed to contribute to the genesis of ARL: 1) loss of immunoregulation of EBV+ B cells resulting from impaired T cell function late in the course of HIV disease, and 2) chronic B cell activation leading to DNA-modifying events that contribute to oncogene mutations/translocations. Therefore, both chronic B cell activation and impaired CD8 T cell function are important contributors to lymphomagenesis. Recently, two different groups described a subpopulation of CD8+ T cells that expresses CXCR5 (the receptor for CXCL13) in the LCMV model, a mouse model of chronic viral infection. In these studies, this novel population of CD8+CXCR5+ T cells, also called follicular CD8 (fCD8+) T cells, were shown to express PD1, and were seen to be LCMV-specific and located in secondary lymphoid tissues. Additionally, fCD8+ T cells were recently shown to be present in tumors and to promote B cell activation. Moreover, large numbers of fCD8+ T cells have been observed in a lymphoma mouse model. Inflammation and immune activation may be responsible for driving the accumulation of fCD8+ T cells in the B cell follicles, since there is an accumulation of inflammatory cells and CXCL13 in lymph nodes of HIV+ individuals. Since inflammation and microbial translocation precede ARL development and play an important role in lymphomagenesis, it is reasonable to think that inflammation and microbial translocation may be important in the accumulation of fCD8+ T cells in HIV infection. fCD8+ T cells may also play a role in the development and maintenance of the tumor niche. Together, this had led us to hypothesize that fCD8+ T cells, which are known to be elevated in HIV infection, result from inflammation/microbial translocation, are part of the tumor niche, and induce B cell activation contributing to lymphomagenesis and tumor growth, as well as B cell dysfunction. In this study, we will test this hypothesis by determining if: 1) fCD8+ T cells from HIV-negative and HIV+ individuals induce B cell activation and/or Breg cells, both present prior to ARL diagnosis (aim 1), 2) immune activation-associated inflammation and/or microbial translocation contribute to the generation of fCD8+ T cells and if fCD8+ T cells are present in gut associated lymphoid tissue in HIV+ individuals, the site where microbial translocation/inflammation take place (aim 2), and 3) fCD8+ T cells function as part of the tumor micro-environment in ARLs and defining how they may be contributing to tumor development (aim 3).
Chronic B cell activation contributes to the genesis of AIDS-related non-Hodgkin's lymphoma (ARL), and CD8+ T cell dysfunction may contribute to the growth ARLs, many of which are EBV-positive. The studies outlined in this proposal aim to determine whether CD8+CXCR5+ T cells, termed follicular CD8 (fCD8+) T cells, which are elevated in HIV infection, contribute to the tumor niche and induce oncogenic molecular changes in B cells, and/or support the growth of ARL cells, thereby promoting lymphomagenesis and tumor growth.
