Interleukin 21–Induced Granzyme B–Expressing B Cells Infiltrate Tumors and Regulate T Cells

Abstract

The pathogenic impact of tumor-infiltrating B cells is unresolved at present, however, some studies suggest that they may have immune regulatory potential. Here, we report that the microenvironment of various solid tumors includes B cells that express granzyme B (GrB, GZMB), where these B cells can be found adjacent to interleukin (IL)-21-secreting regulatory T cells (Treg) that contribute to immune tolerance of tumor antigens. Because Tregs and plasmacytoid dendritic cells are known to modulate T-effector cells by a GrB-dependent mechanism, we hypothesized that a similar process may operate to modulate regulatory B cells (Breg). IL-21 induced outgrowth of B cells expressing high levels of GrB, which thereby limited T-cell proliferation by a GrB-dependent degradation of the T-cell receptor z-chain. Mechanistic investigations into how IL-21 induced GrB expression in B cells to confer Breg function revealed a CD19

Human regulatory B cells in health and disease: therapeutic potential

“…This approach has already proven highly effective in the treatment of various cancers, with its low toxicity and increased ability to eradicate tumors (74). ian carcinomas (14). These findings are particularly significant, as they confirm the existence of B cells with a regulatory phenotype in solid tumor infiltrates, where they would suppress antitumor immune responses.…”

“…Multiple subsets of B cells that produce IL-10, often with overlapping surface markers but diverse functions, have been reported and are collectively referred to as Bregs (12 + B cells, which have all been shown to suppress proinflammatory responses (4,(13)(14)(15)(16). Notably, fewer than 20% of the B cells within these different B cell subsets produce IL-10 and suppress immune responses.…”

Antiviral Vaccines License T Cell Responses by Suppressing Granzyme B Levels in Human Plasmacytoid Dendritic Cells

“…As we and others have shown, pDC are able to express and secrete a series of molecules with immunomodulatory effects on T cells including IDO (36), ICOS ligand (37), and GrB (6). GrB takes an exceptional position in this context because it was shown to be necessary for the function of regulatory T cells (22,38) and to be expressed by other regulatory cell subsets such as human regulatory B cells (39). Furthermore, we could demonstrate in our recent study that pDC activated with IL-3 and IL-10 produce substantially more GrB on a per-cell basis than cytotoxic cells and that pDC are able to efficiently suppress both CD4…”

Granzymes Regulate Proinflammatory Cytokine Responses

“…Gr expression could therefore depend on the developmental stage of the DC, because mature pDCs do not express GrA (57). Human B cells also express GrB (63)(64)(65), and as for DCs, GrB expression is induced by IL-21, albeit in the context of other stimuli, including viral Ags (65). GrB from B cells was shown to inhibit T cell proliferation via the cleavage of the TCR z-chain (63), an extracellular and perforinindependent mechanism also shown for GrB derived from cytotoxic lymphocytes (66).…”