Regulatory B cells (Bregs) have been shown to ameliorate lupus, multiple sclerosis, inflammatory bowel disease, allergy and transplant rejection via cytokines such as interleukin-10 (IL-10) and IL-21 (1-4). There is currently no therapy, which augments Breg populations in vivo.
Analysis of published genome-wide expression data of Bregs suggested an upregulation of components of the IL-2 receptor, CD25 and CD122 (5). CD25 and CD122 on human blood and splenic B cells as well murine splenic B cells were examined by flow cytometry and found to be co-expressed following stimulation of toll-like receptors (TLR) and CD40. Thus, B cells can be receptive to IL-2.
To understand the effects of IL-2 on B cells, negatively isolated human and murine splenic B cells were stimulated with combinations of TLR and CD40 ligands along with IL-2. IL-10 production was drastically augmented with IL-2 in a dose dependent manner. Moreover, pro-inflammatory cytokines such as IL-6 and tumour necrosis factor alpha (TNF-α) were unchanged resulting in a skewing of B cells towards anti-inflammation. Co-culture of IL-2-treated B cells with stimulated CD4 cells produced a reduction in T cell production of TNF-α. Using small molecule inhibitors and ‘phosphospecific’ antibodies directed at molecule downstream of the IL-2 receptor suggest a predominantly PI3K-mediated phenomenon.
To assess the in vivo relevance, BALB/c splenocytes were transferred into BL/6 mice with or without IL-2. Mice receiving IL-2 had greater proportion transitional CD21/23high or CD9high B cells, both of which are populations known to be heavily enriched in Bregs.
Finally, on-going initial analysis of peripheral blood B cells from human subjects with autoimmune diseases who received low-dose IL-2 (Proleukin) suggest increase in CD9-expressing- and IL-10-producing B cells.
1. Menon. Immunity 15 (2016).
2. Shen. Nature 507 (2012).
3. Yoshizaki. Nature 491 (2012).
4. Khan. Nature Communications (2015).
5. van de Veen. J Allergy Clin Immunol 131 (2013).