Magdalena Hagn

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

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.

CD5+ B cells from individuals with systemic lupus erythematosus express granzyme B

Recently, we reported that IL‐21 induces granzyme B (GzmB) and GzmB‐dependent apoptosis in malignant CD5+ B cells from patients with chronic lymphocytic leukemia. Several autoimmune diseases (AD) are associated with enhanced frequencies of CD5+ B cells. Since AD are also associated with elevated IL‐21 and GzmB levels, we postulated a link between CD5+ B cells, IL‐21 and GzmB. Here, we demonstrate that IL‐21 and GzmB serum levels are highly correlated in subjects with systemic lupus erythematosus (SLE) and that freshly isolated CD5+ SLE B cells constitutively express GzmB. IL‐21 directly induced GzmB expression and secretion by CD5+ B cells from several AD and from cord blood in vitro, and the simultaneous presence of BCR stimulation strongly enhanced this process. Furthermore, IL‐21 suppressed both viability and expansion of CD5+ B cells from SLE individuals. In summary, our study may explain the elevated levels of IL‐21 and GzmB in SLE and other AD. Moreover, our data suggest that IL‐21 may have disease‐modifying characteristics by inducing GzmB in CD5+ B cells and by suppressing their expansion. Our results provide the rationale for further evaluation of the therapeutic potential of IL‐21 in certain AD such as SLE.

CD27(+)IgD(-) B cells in the peripheral blood of colorectal cancer patients: on anti-tumor or tumor-protective mission?

In their recent study published in Oncotarget Shimabukuro-Vornhagen and colleagues present interesting data on tumor-associated B cell subsets in patients with colorectal cancer [1]. The authors noted a significantly higher frequency of CD27+IgD− B cells in the peripheral blood of such patients as compared to healthy subjects. The results were interpreted as a specific B cell immune response against the tumor, resulting in the accumulation of terminally differentiated memory B cells or plasma cells. Since the phenotype of B cells may not be sufficient to safely predict their function, we would like to suggest an alternative explanation for the occurrence of CD27+IgD− B cells in these patients. In a recent study, we screened the tumor microenvironment of various tumors for a novel regulatory B cell subset characterized by unique expression of the serine protease granzyme B (GrB) and potent GrBdependent T cell-suppressive activity [2]. We found that several tumor entities including colorectal, mamma, cervical and ovarian carcinomas contain significant numbers of GrB-expressing regulatory B cells. Notably, further phenotypic characterization of this GrB+ regulatory B cell subset showed enhanced expression of CD27, CD38, IgM, CD1d, CD86 and CD147. In contrast, expression of IgD and CD24 was downmodulated or unaltered in this novel regulatory B cell subset. The phenotype of GrB+ regulatory B cells is therefore in part similar to that of terminally differentiated plasma cells, a finding also reported by several independent groups working on distinct regulatory B cell subsets such as IL- 10-secreting regulatory B cells [3, 4]. The reason for this phenotypic similarity between regulatory B cells and plasma cells may be that both B cell populations share a key cytokine for their development, namely interleukin 21 (IL-21) [2, 5-7]. As previously shown by our group it depends on a second T cell-derived stimulus, CD40 ligand (CD40L), whether IL-21 drives B cells to differentiate into GrB-secreting regulatory B cells (in the absence of CD40L), or into antibody-secreting plasma cells (in the presence of CD40L) (Figure ​(Figure1)1) [8, 9]. Figure 1 B cell differentiation in the presence of full T cell help as compared to incomplete T cell help Meanwhile it is widely accepted that B cells exhibit a broad spectrum of functions beyond antibody secretion including T cell regulation, antigen presentation, cytokine production and direct cytotoxicity. Functional assays accompanying the phenotypic characterization of B cell populations may therefore avoid conflicting results on distinct functions of certain B cell subsets, particularly in an aberrant microenvironment such as in the presence of tumors.