Surprisingly, even though elevated GC B cell frequencies were readily detectable in TB-KO mice upon SRBC immunization (Fig.?5a), there was no further increase in GC B cell numbers Xanthohumol in TB-KO mice compared to those observed in B-KO mice (Fig.?5b). by contrast, loss of miR-146a in T cells does not alter humoral responses. However, specific deletion of both miR-146a and its paralog, miR-146b, in T cells increases Tfh cell numbers and enhanced GC reactions. Thus, our data reveal differential cell-intrinsic regulations of GC B and Tfh cells by miR-146a and miR-146b. Together, members of the miR-146 family serve as crucial molecular brakes to coordinately control GC reactions to generate protective humoral responses without eliciting unwanted autoimmunity. Introduction To combat enormously diverse microbial pathogens, different cellular and molecular players need to work in cooperation with, or sometimes in opposition to each other to generate effective immunity. When first-line innate immune responses fail to control contamination, B and T cells work in synergy to mount humoral and cellular adaptive immune responses. In the absence of B cells, T cells Xanthohumol display poor priming and impaired clonal growth upon antigen stimulation1. Likewise, absent T cells, mice fail to develop germinal centers (GCs), where memory B cells and high affinity antibody-producing plasma cells are generated2. The reciprocal dependency between these two major immune cell subsets has become even more evident with the discovery of a specialized T cell subset known as follicular helper T (Tfh) cells3. Tfh cells express elevated levels of the chemokine receptor CXCR5, which allows them to respond to CXCL13 and migrate into B cell follicles. The colocalization and conversation between Tfh and B cells are crucial for the induction of the GC reaction, the production of specialized, high affinity antibodies, and the generation of long-term protective immunity. The identification of transcription repressor Bcl6 as a key transcription factor in Tfh cell differentiation CXCR7 has further substantiated the notion that Tfh cells comprise a distinct T helper cell lineage similar to Th1, Th2, Th17, or regulatory T (Treg) cells3. Interestingly, Bcl6 was originally identified as an essential regulator of GC B cell differentiation4. The fact that Bcl6 controls the development of both GC B cells and Tfh cells suggested a common gene regulatory circuit can be implemented in different immune populations to enable them to play their specialized functions in producing a concerted response to a particular environmental stimulus. Like Bcl6, microRNA (miR)-146a was shown to be highly expressed in both Tfh and GC B cells5. Recent studies have showed that miR-146a plays a prominent role Xanthohumol in different aspects of immune cell biology6. Both Toll-like receptor (TLR) signaling and Th1 cytokines can strongly upregulate miR-146a expression levels in myeloid cells and Th1 cells, respectively7,8. In turn, miR-146a limits the activation and the function of the aforementioned immune cells through repressing key molecules downstream of the corresponding signaling pathways7,9. Considering the fact that dysregulated humoral immune responses and heightened production of autoantibodies have been previously reported in mice devoid of miR-146a10,11, it is thus conceivable that this elevated levels of miR-146a detected in both Tfh and GC B cells might also be Xanthohumol essential to restrain the responses of these two immune cell populations. Indeed, two recent studies have implicated miR-146a as a negative regulator of Tfh cell responses11,12. Specifically, it was suggested that miR-146a was able to limit the accumulation of Tfh cells and the resultant germinal center responses by directly targeting ICOS12. Similarly, a potential involvement of miR-146a in controlling B cell responses has also been proposed11,13. Nevertheless, clear mechanistic insights into miR-146a-mediated B cell regulation are still lacking. More importantly whether miR-146a plays a non-redundant B cell-intrinsic role in maintaining optimal GC responses and preventing the development of autoimmunity remains to be further determined. To directly examine the function of miR-146a in regulating B cell responses, we generated mice harboring a conditional allele of miR-146a, which allows for cell-type-specific miR-146a ablation. Our results demonstrate that miR-146a deletion in B cells alone is sufficient to lead to the development of spontaneous GC responses and the production of autoantibodies as mice aged. Upon immune challenges, Xanthohumol exaggerated GC reactions observed in mice harboring miR-146a-deficient.