Nonredundant Roles for B Cell-Derived IL-10 in Immune Counter-Regulation

Abstract

IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8+ T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.

Cognate interaction with iNKT cells expands IL-10–producing B regulatory cells

“…5). We obtained these results using VertX IL-10 reporter mice, which accurately report IL-10 production using a bicistronic GFP reporter downstream of the IL-10 gene (42). LPS immunization confirms the reliability of these mice, inducing significantly more IL-10-producing B cells over vehicle-immunized mice after 2 days (Fig.…”

Intratumor OX40 stimulation inhibits IRF1 expression and IL‐10 production by Treg cells while enhancing CD40L expression by effector memory T cells

“…BM chimeras were generated such as to carry an IL-10-GFP reporter transgene [22] in the hemopoietic lineage. IL-10-GFP expression, evaluated in tumor-infiltrating CD4 1 CD25 high Treg cells, was significantly reduced after intratumoral OX86 injection ( Fig.…”

“…Female (BALB/c  C57BL/6) F1 mice were irradiated at 6001 600 Rad with an interval of 3 h and received 10 7 BM cells from IL-10-GFP C57BL/6 female mice [22], provided by Giorgio Trinchieri (NCI, Frederick). After 8 wk correct reconstitution was checked by flow cytometry, after staining peripheral blood cells with PE anti-K d , PE-Cy7 anti-CD4 and allophycocyanin antiFoxp3.…”

Novel Highly Sensitive IL-10–β-Lactamase Reporter Mouse Reveals Cells of the Innate Immune System as a Substantial Source of IL-10 In Vivo

“…Taken together, this intrinsic instability of Il10 mRNA results in low and transient expression of IL-10 protein and consequently restricts the sensitivity of a reporter gene like EGFP that is known to have a high limit of detection (∼10 5 molecules/cell) (7). Recently, IL-10 reporter mouse models, 10BiT, Vert-X, and Il10 Venus mice, have been reported in which the authors tried to overcome this limitation by exchanging the mRNA-destabilizing Il10-39 UTR for the SV40 early intron-polyA (SV40 polyA) that ensures mRNA stability of the corresponding reporter genes (37,45,46). Although these reporter mouse models indeed showed improved reporter activity, they lack a decisive posttranscriptional regulating element, the Il10-39 UTR.…”

“…The data shown are representative of results obtained by using three to five mice. responses (34)(35)(36)(37). Thus, a successful therapeutic use of IL-10 has also to take into account the IL-10-producing cell types under given physiological and immunological conditions; for example, by developing drugs that specifically control, temporally and locally, IL-10 production by a given cell type.…”