Killer B Cells: Regulation of the Growth and Function of Fas Ligand-Expressing B Lymphocytes.

Abstract

The immune system is a highly-specialized cellular network that must respond to a wide variety of microbial species while remaining tolerant of an organism’s own cells and tissues. Loss of self-tolerance can lead to immune-mediated tissue destruction and disease, and therefore regulatory mechanisms have evolved that inhibit immune responses to self-antigens. The work presented in this dissertation sought to better understand the biology of B cells that express the death-inducing molecule Fas ligand (FasL), a potentially important regulatory B cell population. Conceptually, FasL+ “killer” B cells are unique amongst regulatory B cells as they possess the potential for suppression that is both antigen-specific and permanent. The experiments herein identified a novel antagonistic relationship between the type-2 cytokines interleukin-5 (IL-5) and IL-4 regarding their effects on FasL+ B cell function. Treating murine B cells with IL-5 expanded a population of B cells with potent killing activity against CD4+ T cells and that secreted the anti-inflammatory cytokine IL-10. In contrast, treatment with IL-4 inhibited both of these regulatory mechanisms in B cells. Therefore, drugs that activate pathways downstream of the IL-5 receptor or inhibit those downstream of the IL-4 receptor may lead to novel areas of drug discovery for the treatment of immune-mediated disorders. Although FasL+ B cells are rare in vivo, lymphoblastoid cell lines (LCLs) generated by transformation of human B cells with Epstein-Barr virus (EBV) showed robust expression of intracellular FasL, suggesting that the EBV latency program in transformed B cells drives the production of FasL. LCLs also secreted MHCII+FasL+ exosomes that induced antigen specific apoptosis in CD4+ T cells in two independent experimental designs. LCLs consequently represent a realistic source for immuosuppressive exosomes for therapeutic use in the treatment of human disease. This study has therefore set the groundwork for future investigations that may one day lead to powerful and novel therapeutic strategies.