Abstract Regulatory B cells (Breg) are vital for inflammation and tissue injury resolution. Here, we investigated the role of transforming growth factor-β1 (TGF-β1)-producing Breg in the murine model of ventilation-induced lung injury (VILI). The percentages of pulmonary CD19highCD44(+) TGF-β1(+) Breg were increased at PV1d and PV10d in VILI mice. Lung injury and inflammation were attenuated by up-regulating TGF-β1 levels with regulation of T-cell immunity. To prolong and stabilize the effect of exogenous TGF-β1, macrophage-derived microvesicles-coated nanoparticles (MNP) loaded TGF-β1(TMNP) were synthesized, and VILI mice were divided into sham, recombinant TGF-β1 (rTGF-β), MNP, and TMNP groups. TMNP increased the TGF-β1 levels in serum and lung tissues at PV10d. Compared with rTGF-β group, lung injury and inflammation in TMNP group at PV1d were attenuated with Breg proliferation; TMNP induced the reduction of pulmonary CD4(+) T cell proportions and CD4(+)/CD8a(+) T cell ratios, but promoted the proliferation of pulmonary CD8a(+) T cells at PV1d and PV10d. Together, TMNP promote the resolution of inflammatory lung injury, which may be associated with the proliferation of Breg to maintain immunological homeostasis.

Crlz-1 was expressed along with Wnt3a in the rapidly proliferating centroblasts within the dark zone of germinal center (GC) during humoral immune responses. Significantly, Crlz-1 relayed a Wnt/β-catenin signal to the expression of Bcl-6, the master regulator of centroblasts, by mobilizing the cytoplasmic CBFβ into the nucleus to allow Runx/CBFβ heterodimerization and its subsequent binding to the Bcl-6 promoter. The knockdown of Crlz-1 or β-catenin, as well as inhibition of Wnt signaling in the centroblasts, led to the decreased expression of Bcl-6 and, thereby, the altered expression of its various target genes, resulting in their diminished proliferation. Consistently, the administration of Wnt inhibitors into the immunized mice impaired or abolished GC reaction, with concomitant decreases of Crlz-1 and Bcl-6 expression and, thus, centroblastic proliferation. Our observation that Wnt/β-catenin signaling via Crlz-1 regulates GC reaction would suggest developmental strategies for vaccine adjuvants and cancer therapeutics because both immune efficacy and accidental lymphoma depend on GC reaction. Our studies of Crlz-1 were performed using human cell lines, mice, and their primary cells.
Copyright © 2019 by The American Association of Immunologists, Inc.