Mir-17–92 regulates bone marrow homing of plasma cells and production of immunoglobulin G2c

Abstract

The polycistronic mir-17-92 cluster, also known as oncomir-1, was previously shown to be essential for early B lymphopoiesis. However, its role in late-stage B-cell differentiation and function remains unexplored. Here we ablate mir-17-92 in mature B cells and demonstrate that mir-17-92 is dispensable for conventional B-cell development in the periphery. Interestingly, mir-17-92-deficiency in B cells leads to enhanced homing of plasma cells to the bone marrow during T-cell-dependent immune response and selectively impairs IgG2c production. Mechanistically, mir-17-92 directly represses the expression of Sphingosine 1-phosphate receptor 1 and transcription factor IKAROS, which are, respectively, important for plasma cell homing and IgG2c production. We further show that deletion of mir-17-92 could reduce IgG2c anti-DNA autoantibody production and hence mitigate immune complex glomerulonephritis in Shp1-deficient mice prone to autoimmunity. Our results identify important roles for mir-17-92 in the regulation of peripheral B-cell function.

miRNAs in B Cell Development and Lymphomagenesis

“…A study examining the functional role of the miR-17~92 cluster in late B cells revealed its potential importance in plasma cells [62] (thus, important not only in early B cell development and tolerance [30, 31, 40]). Indeed, conditional deletion of this cluster in mature B cells using CD19-Cre mice resulted in increased plasma cell homing to the BM upon immunization with a T-independent antigen, suggesting that this miRNA cluster regulated homing of plasma cells to their natural niche [62].…”

“…Indeed, conditional deletion of this cluster in mature B cells using CD19-Cre mice resulted in increased plasma cell homing to the BM upon immunization with a T-independent antigen, suggesting that this miRNA cluster regulated homing of plasma cells to their natural niche [62]. Speciffically, the data indicated that the sphingosine 1-phosphate receptor 1 (S1PR1), a receptor for S1P, was a target of different members of the miR-17~92 cluster in B cells [62]. The S1PR1-S1P signaling pathway had been previously shown to be critical for immune cell migration from secondary lymphoid organs to the BM [63].…”

“…The S1PR1-S1P signaling pathway had been previously shown to be critical for immune cell migration from secondary lymphoid organs to the BM [63]. Conditional ablation of one copy of s1pr1 in CD19 positive B cells reversed the phenotype of miR-17~92 deficient plasma cells, where homing of plasma cells to the BM was restored to the degree resembling that of control animals [62]. The report concluded that miR-17~92 could affect homing of plasma cells in the BM by reducing the levels of S1PR1 on plasma cells[62].…”

“…Conditional ablation of one copy of s1pr1 in CD19 positive B cells reversed the phenotype of miR-17~92 deficient plasma cells, where homing of plasma cells to the BM was restored to the degree resembling that of control animals [62]. The report concluded that miR-17~92 could affect homing of plasma cells in the BM by reducing the levels of S1PR1 on plasma cells[62]. This finding is important, as homing to the BM allows for the long-term longevity of plasma cells, key to enabling efficient immune responses [64].…”

“…This finding is important, as homing to the BM allows for the long-term longevity of plasma cells, key to enabling efficient immune responses [64]. Moreover, ablation of miR-17~92 in antigen-activated B cells led to reduced CSR into the IgG2c isotype as a consequence of upregulated Ikaros mRNA and protein expression[62]. In vitro luciferase assays also revealed that Ikaros ( Ikzf1 ) was specifically targeted by miR-92 [62].…”