Funktion und pathophysiologische Bedeutung Granzym B-exprimierender regulatorischer B-Zellen

Abstract

Human B cells have the ability to express the serine protease granzyme B (GrB) in response to the stimulation with Interleukin 21 (IL-21), a cytokine primarily found in the acute phase of infections. These GrB+ B cells can exhibit regulatory potential. Our experiments show that GrB+ B cells were found in the microenvironment of solid tumors and also have regulatory effects on T cell proliferation. This phenomenon resembles the effect of regulatory T cells (Treg). To verify the regulatory function of GrB+ B cells, we characterized the molecular mechanism of the suppression of T cell proliferation. A direct substrate of Granzym B is the T cell receptor zeta chain, which is essential for the signal transduction in T cells. We could demonstrate that B cells expressing GrB after stimulation with IL-21, degrade the TCR zeta chain of CD4+ T cells. Furthermore these GrB+ B cells also express regulatory molecules like IDO and IL-10. To support our findings in vivo, we screened different pathological tissues such as colorectal-, prostate- or breast carinomas. We were able to show the existence of GrB+ B cells in all screened tissues, which is dependent on the presence of IL-21 in these tumors. We also found IL-10 expressing B cells in the tumor microenvironment. This indicates a regulatory effect of GrB+ B cells in cancer immunity. Our findings could have significant implications on our understanding of the role of B cells in immune regulation and for a broad variety of immune phenomena including auto-, cancer and infectious immunity.