Elevation in the counts of IL-35-producing B cells infiltrating into lung tissue in mycobacterial infection is associated with the downregulation of Th1/Th17 and upregulation of Foxp3+Treg

Abstract

IL-35 is an anti-inflammatory cytokine and is thought to be produced by regulatory T (Treg) cells. A previous study found that IL-35 was upregulated in the serum of patients with active tuberculosis (ATB), and IL-35-producing B cells infiltrated to tuberculous granuloma of patients with ATB. Purified B cells from such patients generated more IL-35 after stimulation by antigens of Mycobacterium tuberculosis and secreted more IL-10. However, the function and the underlying mechanisms of IL-35-producing B cells in TB progression have not been investigated. The present study found that the expression of mRNA of IL-35 subsets Ebi3 and p35 was elevated in mononuclear cells from peripheral blood, spleen, bone marrow, and lung tissue in a mouse model infected with Mycobacterium bovis BCG, as tested by real-time polymerase chain reaction. Accordingly, the flow cytometry analysis showed that the counts of a subset of IL-35 + B cells were elevated in the circulating blood and in the spleen, bone marrow, and lung tissue in BCG-infected mice, whereas anti-TB therapy reduced IL-35-producing B cells. Interestingly, BCG infection could drive the infiltration of IL-35-producing B cells into the lung tissue, and the elevated counts of IL-35-producing B cells positively correlated with the bacterial load in the lungs. Importantly, the injection of exogenous IL-35 stimulated the elevation in the counts of IL-35-producing B cells and was associated with the downregulation of Th1/Th17 and upregulation of Foxp3 + Treg.The study showed that a subset of IL-35-producing B cells might take part in the downregulation of immune response in mycobacterial infection.

Immunosuppressive Mechanisms of Regulatory B Cells

“…These cells, named IL-35 + Bregs, develop spontaneously in mice with experimental autoimmune uveitis (EAU), exhibit a CD1d hi CD21 hi phenotype, and are a major source of IL-35. Furthermore, IL-35 + Bregs are expanded in vivo upon injection of IL-35, which is associated with an increase in Tregs, and a decrease in Th1 and Th17 cells via IL-10 and IL-35 production, reducing the severity of EAU ( 89 , 356 ), but impairing protective immunity in a mycobacterial infection model ( 357 ). In parallel, Shen et al described the ability of CD40 and TLR4 stimulation to induce IL-35 production by murine B cells.…”

Gut microbiota–derived metabolite 3-idoleacetic acid together with LPS induces IL-35+ B cell generation

“…This cytokine has strong suppressive properties both in vivo and in vitro [ 22 – 24 ]. It can exert wide-ranging effects on multiple types of immune cells, such as T cells, B cells, macrophages, and dendritic cells (DCs) [ 19 ], promote the generation of Treg cells and anti-inflammatory macrophage 2 (M2) [ 25 , 26 ], and impede the differentiation of Th1 cells [ 27 ]. The expression of IL-35 is dysregulated in inflammatory autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, and experimental autoimmune uveitis [ 28 ].…”

A century of BCG: Impact on tuberculosis control and beyond

“…119 Similar to active Mtb infection BCG inoculation has been shown to increase Treg frequencies in animal models as well as human studies (Figure 1). [120][121][122][123] This increase in Treg frequencies postadministration of BCG is believed to reduce its vaccination efficacy. 124,125 Absence of Tregs in BCG-vaccinated mice leads to higher cytotoxic T cell and Th1 responses 125 and marginally but significantly reduced bacterial burden postchallenge with Mtb.…”