Macrophage polarization to a unique phenotype driven by B cells.

Regulation of adaptive immunity by innate immune cells is widely accepted. Conversely, adaptive immune cells can also regulate cells of the innate immune system. Here, we report for the first time the essential role of B cells in regulating macrophage (M phi) phenotype. In vitro B cell/M phi co-culture experiments together with experiments in transgenic mice models for B-cell deficiency or overexpression showed B1 cells to polarize M phi to a distinct phenotype. This was characterized by downregulated TNF-alpha, IL-1 beta and CCL3, but upregulated IL-10 upon LPS stimulation; constitutive expression of M2 M phi markers (e.g. Ym1, Fizz1) and overexpression of TRIF-dependent cytokines (IFN-beta, CCL5). Mechanistically, this phenotype was linked to a defective NF-kappa B activation, but a functional TRIF/STAT1 pathway. B1-cell-derived IL-10 was found to be instrumental in the polarization of these M phi. Finally, in vivo relevance of B1-cell-induced M phi polarization was confirmed using the B16 melanoma tumor model where adoptive transfer of B1 cells induced an M2 polarization of tumor-associated M phi. Collectively, our results define a new mechanism of M phi polarization wherein B1 cells play a key role in driving M phi to a unique, but M2-biased phenotype. Future studies along these lines may lead to targeting of B1 cells to regulate M phi response in inflammation and cancer.