IL-10 plays a central role in restraining the vigor of inflammatory responses, but the critical cellular sources of this counter-regulatory cytokine remain speculative in many disease models. Using a novel IL-10 transcriptional reporter mouse, we found an unexpected predominance of B cells (including plasma cells) among IL-10-expressing cells in peripheral lymphoid tissues at baseline and during diverse models of in vivo immunological challenge. Use of a novel B cell-specific IL-10 knockout mouse revealed that B cell-derived IL-10 nonredundantly decreases virus-specific CD8+ T cell responses and plasma cell expansion during murine cytomegalovirus infection and modestly restrains immune activation after challenge with foreign Abs to IgD. In contrast, no role for B cell-derived IL-10 was evident during endotoxemia; however, although B cells dominated lymphoid tissue IL-10 production in this model, myeloid cells were dominant in blood and liver. These data suggest that B cells are an underappreciated source of counter-regulatory IL-10 production in lymphoid tissues, provide a clear rationale for testing the biological role of B cell-derived IL-10 in infectious and inflammatory disease, and underscore the utility of cell type-specific knockouts for mechanistic limning of immune counter-regulation.

B cells were previously shown to mediate partial protection against CMV infection, as in the absence of B cells, latently infected mice were more susceptible to virus reactivation. It remains unclear if this eVect stems from the loss of B cells as antibody producers or as antigen presenting cells. To address this fundamental question, we propose to make use of new mouse models that allow conditional ablation of B cells or that allow for the generation of mice with B cells that are not able to produce antibodies. Short history of B cells and CMV infectionCytomegaloviruses (CMVs) are members of the herpesvirus family. CMVs show host species-speciWcity; for instance, human CMV (HCMV) and murine CMV (MCMV) infect humans and mice, respectively. Primary infection with HCMV or MCMV is controlled by the immune system and in particular cytotoxic T cells (CTLs) were shown to play a critical role (for a review see [1]). Like the other members of the herpesvirus family, CMVs cannot be entirely eliminated by the infected host, even if the immune system is intact. After the primary infection is controlled, CMVs remain in reservoirs in a state of latency. The cell types in which the virus persists are yet to be identiWed. In humans as well as in mice, reactivation of latent CMV can occur when the host is immunosuppressed. In immunocompromised or immunosuppressed patients, CMV reactivation can result in invasive CMV disease such as pneumonitis, esophagitis, encephalitis, hepatitis, pancreatitis, adrenalitis, gastritis, enteritis, colitis, and retinitis [2,3]. HCMV is by far the most common infection in solid organ transplant recipients, with over half of the patients showing evidence of active infection (viral replication). In addition to the debilitating eVects of direct, organ-speciWc syndromes such as bilateral interstitial pneumonia, disseminated CMV disease is widely believed to cause graft injury and shorten graft survival [4,5]. Much is known about the factors that control the primary CMV infection, but much less is known about how to control the reactivation of the virus, or in fact which cellular and humoral factors keep the virus inactive after the Wrst infection is resolved.Antibodies were found to have a protective role in mice infected with MCMV [6]. CMV-speciWc serum was administered to infected mice and was shown to partially protect the mice [7]. These results were conWrmed by experiments where serum from infected C57BL/6 mice, but not naïve mice or B-cell deWcient MT mice, showed dramatically reduced virus titers in the salivary glands and blood of infected mice [8]. Moreover, when monoclonal antibodies were used in protection assays, it was found that protection from CMV infection correlates with aYnity to CMV antigens: the antibodies with the higher aYnity protected the mice much better than the antibodies with lower aYnity [9]. To better understand the role of antibodies and B cells in MCMV infection, Jonjic and co-workers investigated CMV infection in the MT mice that lack B cells. Using these muta...

B cells were first discovered as antibody producing cells, as B-1 B cells and finally as effector cells. In recent years their capacity to serve as antigen presenting cells is increasingly appreciated, and better tools are needed to study their function. We have previously described a new mouse model, the iDTR mice, that allow for the Cre-mediated expression of the diphtheria toxin receptor, thus rendering cells that express the Cre-recombinase sensitivity to diphtheria toxin. Herein we describe a new mouse line, the B-DTR mice, where the CD19-Cre was crossed to the iDTR mice. B-DTR allows for the efficient and cost-effective depletion of different B cell subpopulations, but only partially plasma cells. These mice can therefore be used to study the importance of B cells versus plasma cells in different immune responses and autoimmune diseases.

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