Thus, both superabundant or insufficient miR-146a expression are harmful for GC homeostasis. Overall, these studies show that regulated miRNA expression is required to ensure proper GC responses and that GC-derived dysfunctions caused by miRNA alterations frequently lead to the development of both autoimmunity and B cell neoplasia through the disruption of post-transcriptional control mechanisms required for the maintenance of GC homeostasis, regulated cell signaling, cell death and proliferation. a mutation in the miR-155 recognition site in the mRNA 3UTR. miR-155-mediated PU.1 post-transcriptional regulation was shown to be required for efficient terminal plasma B cell differentiation and antigen-specific immunoglobulin (Ig) secretion through the downregulation of expression and genes involved in adhesion and B-T cell interactions (20). The other well characterized miR-155 target in GC B cells is activation-induced deaminase (AID), the enzyme responsible for the molecular remodeling of Igs in the GC. Knock-in mice with a KN-62 disruption of the miR-155 recognition site in the mRNA 3UTR demonstrated that miR-155 expression in GC B cells is needed to limit AID expression, allow proper affinity maturation, and restrict oncogenic AID-mediated MYC-IgH chromosomal translocations (21, 22). GC tolerance of DNA damage is multilayered and temporally regulated (23), and miR-155 expression is in turn limited by the expression of BCL6 (24, 25), an important transcriptional regulator and proto-oncogene that inhibits the DNA damage response in GC B cells (26). In addition, miR-155 negatively regulates the expression of and directly through the binding of several partly complementary sequences found in its mRNA 3UTR (28). Thus, AID levels are controlled by different miRNAs at different stages of B cell activation. Another miRNA that positively regulates the GC response upon its induction during B cell activation and in GC B cells is miR-217. Using gain- and loss-of-function mouse models, we showed that miR-217 promotes the generation of GC B cells and increases the generation of class-switched antibodies and the frequency of somatic hypermutation in KN-62 B cells. We found that miR-217 regulates a DNA damage response and repair gene network that stabilizes BCL6 expression in GC B cells (29). Thus, miR-217 downregulates a network of genes that sense and repair genotoxic events on DNA, which in turn can increase KN-62 GC B cell tolerance to DNA damage in the context of AID activity, very much like BCL6. Notably, we found that miR-217 protects BCL6 from previously described genotoxic stress-induced degradation (23), suggesting that both molecules form part of the same network that renders GC cells permissive to genomic instability and prone to malignant transformation. Positive regulation of terminal post-GC plasma B cell differentiation has been suggested to be regulated by other miRNAs. A likely candidate is miR-148a, the most abundant miRNA in human and murine plasma cells, which has been shown to promote plasma cell differentiation and survival Importantly, miR-148a expression was shown to downregulate the expression of the GC transcription factors and would require the development of gain- or loss-of-function miR-148a B cell-specific mouse models. GC miRNAs can also act as regulators that restrict the GC response, the best-characterized negative regulators of GC responses being miR-28 and miR-146a. miR-28 is a GC-specific miRNA (14, 15) whose expression is lost in numerous mature B-cell KN-62 neoplasms (31C33). By combining gain- and loss-of-function approaches, we showed that miR-28 negatively regulates CSR and immunization-triggered GC and post-GC plasma and memory B cell generation. Combined transcriptome and proteome analysis upon inducible re-expression of miR-28 in B cells KN-62 revealed that miR-28 expression induces the coordinated downregulation of the key BCR signaling gene network regulating B-cell proliferation and cell death (33), thus supporting the notion that miR-28 limits the strength of BCR signaling and regulates proliferation and survival of GC B cells. miR-146a is expressed in B cells upon stimulation and within GC B cells (15), and loss of miR-146a causes a B cell-intrinsic increase in the GC response to immunization (34), spontaneous GC generation in aged mice, and increased production of anti-doubleCstranded DNA (dsDNA) auto-antibodies (35). miR-146a was shown to limit B cell GC functional responses by downregulating B cell expression of signaling pathway components involved in GC B Tfh cellular interactions, such as ICOSL (34) and CD40 (35). Other miRNAs have also been Bmp7 suggested to negatively regulate terminal post-GC plasma and memory B cell differentiation. miR-125b, a miRNA highly expressed in dividing centroblasts in GC B cells (36), has been shown to inhibit plasma cell generation and antibody secretion (37, 38). Importantly, direct mRNA targeting by miR-125b was shown to downregulate the expression of BLIMP-1 and IRF-4 transcription factors, which are essential for plasma cell differentiation (36C39). and (51). Regulates differentiation and enhances ICOS-PI3K signaling by downregulating and phosphatase gene expression in Tfh cells (10, 48, 49).miR-155 ?Positive GC regulator B cell-intrinsic (12, 17, 18) and T cell-intrinsic mechanisms (52). Prevents LZ GC c-MYC+ B cell apoptosis by downregulating (19). Targets (17, 60) and (21, 22, 44) mRNAs and prevents.