IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice

Abstract

The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB) strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT) cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain. Subsequently, it was shown that CD5+ B cells but not NKT cells derived from these mice could suppress the development of pro-inflammatory T cells. In this paper, we aimed to further resolve the genetics that leads to expansion of these two innate-like populations through the creation of additional sub-congenic mice and to characterize the role of IL-10 in the suppression of autoimmunity through the generation of IL-10 knockout mice. We show that expansion of CD5+ B cells and NKT cells localizes to a chromosome 4 interval spanning 91 to 123 Mb, which is distinct from the region that mediates the majority of the suppressive phenotype. We also demonstrate that IL-10 is critical to restraining autoantibody production and surprisingly plays a vital role in supporting the expansion of innate-like populations.

Cytokine Autoantibodies Are Associated with Infection Risk and Self-Perceived Health: Results from the Danish Blood Donor Study

“…It should be emphasized that the effects of IL-10 c-aAb are likely highly context-specific, as another previous study from our research group reported that IL-10 c-aAb were associated with increased risk of major adverse cardiovascular events (MACE) in kidney-transplanted patients, an outcome that is intrinsically linked to a pro-inflammatory environment [33]. Thus, though protective in regard to infections in healthy individuals, IL-10 c-aAb may constitute a risk factor for patients in whom excess inflammation may tip a balance towards adverse events such as organ transplant patients and autoimmune disease in general, again due to the cytokines' many immunoregulatory functions [34,35]. Conversely, c-aAb against pro-inflammatory cytokines IFNα and IL-1α have been linked to improved prognoses in autoimmune disease [6].…”

Early Generated B-1–Derived B Cells Have the Capacity To Progress To Become Mantle Cell Lymphoma–like Neoplasia in Aged Mice

“…In the NZB background, the presence of autocrine IL-10 by B1a cells was found to be critical for expansion to become lymphoma since IL-10 knockout strongly decreased CD5 + B lymphoma incidence (59). Furthermore, autocrine IL-10 prevented original autoantibody production by B1a cells in NZB mice (61). As shown here, ATA B lymphoma in C.B17 mice also showed high expression of IL-10.…”

Metastatic colon adenocarcinoma has a significantly elevated expression of IL-10 compared with primary colon adenocarcinoma tumors

“…IL-10 can function to stimulate the immune system by increasing the frequency of cytotoxic CD8C T cells and natural killer cells depending on the other cytokines present within the tumor microenvironment (IL-2 for T cell activation and IL-19 for Natural killer cell activation). 26,27 The anti-tumor effects of IL-10 are also demonstrated as IL-10 modifies and efficiently regulates the quality of antigen presentation. 20 The effects of IL-10 within the primary tumor are modulated by the surrounding cytokine profile and expression of the protein can provide insights into approaches the tumor takes to skew the immune response to either anti-inflammatory or pro-inflammatory.…”