Acute Phase Cytokine IL - 21 Recognizing Viral Antigens in the Context of Human B Cells

Human B cells are currently not known to produce the proapoptotic protease granzyme B (GrB) in physiological settings. We have discovered that BCR stimulation with either viral Ags or activating Abs in the context of the acute phase cytokine IL-21 can induce the secretion of substantial amounts of GrB by human B cells. Importantly, GrB response to viral Ags was significantly stronger in B cells from subjects recently vaccinated against the corresponding viruses as compared with unvaccinated subjects. GrB-secreting B cells featured a homogeneous CD19 ؉ CD20 ؉ CD27 ؊ CD38 ؊ IgD ؊ phenotype, improved survival, and enhanced expression of costimulatory, Ag-presenting and cell-adhesion molecules. B cell-derived GrB was enzymatically active and its induction required the activation of similar signaling pathways as those in CTLs. Our findings suggest that GrB-secreting B cells support the early antiviral immune response against viruses with endosomal entry pathways, thereby counteracting overwhelming viral replication at the beginning of an infection until virus-specific T cells from draining lymph nodes arrive at the site of infection. Our data may also explain the elevated serum GrB levels found in the early phase of various viral diseases. F ull activation of virus-specific CTL normally requires the uptake of viral Ags by APC, migration of these APC into the draining lymph nodes, and processing and presentation of Ags by the APC in the context of MHC molecules, a complex process that can take up to several days (1, 2). Therefore a high rate of viral replication may pose a considerable challenge for an antiviral T cell response. In contrast to CTL, B cells can recognize Ags in an immediate and MHC-independent manner. Furthermore, BCR can recognize a larger variety of potential Ags than TCR, including peptide, carbohydrate, glycolipid, and nucleic acid Ags (3, 4). Granzymes such as granzyme B (GrB) 4 represent a major constituent of the granules of CTL (5). The ligation of the TCR by MHC-presented Ag on the target cell, in combination with secondary signals including IL-2, IL-15, and CD28 activation, results in the degranulation of cytotoxic granules and the release of ef-fector molecules such as GrB into the secretory synapse. CTL can deliver GrB to targets such as virus-infected cells, thereby effectively inducing apoptosis (6). Apart from CTL and NK cells, no other normal human lymphocyte population is currently known to produce and secrete active GrB in physiological settings. IL-21, a recently discovered member of …