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.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), commonly known as tubercle bacillus, is a major health problem worldwide, with approximately one third of the global population infected and 10 million new cases reported officially to the World Health Organization in 2 0171,2
For further understanding the roles of IL-35 played in pulmonary tuberculosis, a mouse model was prepared with M. bovis BCG infection (Fig. S1), and mononuclear cells were isolated from peripheral blood, lung, spleen, and bone marrow
Flow cytometry with intracellular cytokine staining (ICS) analysis showed that the frequencies of p35+ and Ebi3+ B cells were much higher in BCG-infected mice than in control mice 2, 4, and 8 weeks after BCG infection, which was consistent with the mRNA expression (Fig. 2)
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), commonly known as tubercle bacillus, is a major health problem worldwide, with approximately one third of the global population infected and 10 million new cases reported officially to the World Health Organization in 2 0171,2. A study reported that M. tuberculosis mannose-capped lipoarabinomannan induces IL-10-producing B cells and hinders CD4+Th1 immunity[25] These findings suggested that IL-10-producing Bregs impaired protective immunity and increased disease severity. A novel subset of Bregs producing an anti-inflammatory cytokine, IL-35, was reported during Salmonella infections and experimental autoimmune encephalomyelitis (EAE). These cells play a key role in immunosuppression[26,27]. A mouse model infected with Mycobacterium bovis bacillus was used to further validate previous findings in patients with TB that Mtb infection could induce the increase in IL-35-producing B cells and their infiltration into TB lesion tissue. It explored the correlation between IL-35-producing B cells and the effector/regulatory T cells in mycobacterial infection
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