The superfamily of tripartite motif-containing (TRIM) proteins is conserved throughout the metazoan kingdom and has expanded rapidly during vertebrate evolution; there are now more than 60 TRIM proteins known in humans and mice. Many TRIM proteins are induced by type I and type II interferons, which are crucial for many aspects of resistance to pathogens, and several are known to be required for the restriction of infection by lentiviruses. In this Review, we describe recent data that reveal broader antiviral and antimicrobial activities of TRIM proteins and discuss their involvement in the regulation of pathogen-recognition and transcriptional pathways in host defence.

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FCMR, a Fc receptor specific for pentameric IgM, is expressed at high levels by B cells. Although circulating IgM has profound effects on responses to pathogens, autoimmunity and B cell homeostasis, the biologic consequences of its binding to FCMR are poorly understood. We interrogated FCMR contributions to B cell function by studying mice lacking FCMR. FCMR transcripts are expressed at different levels by various B cell subsets. FCMR-deficient mice have reduced numbers of developing B cells, splenic FO and peritoneal B-2 cells, but increased levels of peritoneal B-1a cells and autoantibodies. Following immunization, germinal center B cell and plasma cell numbers are increased. FCMR-deficient B cells are sensitive to apoptosis induced by BCR ligation. Our studies demonstrate that FCMR is required for B cell differentiation and homeostasis, the prevention of autoreactive B cells and responsiveness to antigenic challenge.

Previously, it was shown that the CTCF paralogous gene, BORIS (brother of the regulator of imprinted sites) is expressed in male germ cells, but its function in spermatogenesis has not been defined. To develop an understanding of the functional activities of BORIS, we generated BORIS knockout (KO) mice. Mice homozygous for the null allele had a defect in spermatogenesis that resulted in small testes associated with increased cell death. The defect was evident as early as postnatal day 21 and was manifested by delayed production of haploid cells. By gene expression profiling, we found that transcript levels for Gal3st1 (also known as cerebroside sulfotransferase [CST]), known to play a crucial role in meiosis, were dramatically reduced in BORIS KO testes. We found that CST is expressed in testis as a novel testis-specific isoform, CST form F TS , that has a short exon 1f. We showed that BORIS bound to and activated the promoter of CST form F TS . Mutation of the BORIS binding site in the promoter reduced the ability of BORIS to activate the promoter. These findings define transcriptional regulation of CST expression as a critical role for BORIS in spermatogenesis.

The expression of the new Ly108 isoform H1 weakens lupus-like disease of C57BL/6.Sle1b mice.

Transcriptional control of marginal zone (MZ) and follicular (FO) B cell development remains incompletely understood. The transcription factor, IFN regulatory factor (IRF)8, is known to play important roles in the differentiation of early B cells. In this article, we demonstrate that IRF8 is also required for normal development of MZ and FO B cells. Mice with a conventional knockout of Irf8 (IRF8–/–) or a point mutation in the IRF association domain of IRF8 had increased numbers of MZ B cells. To determine the B cell-intrinsic effects of IRF8 deficiency, we generated mice with a conditional allele of Irf8 crossed with CD19-Cre mice (designated IRF8-conditional knockout [CKO]). These mice had enlarged MZ and increased numbers of MZ and FO B cells compared with controls. The FO B cells of CKO mice exhibited reduced expression of CD23 and moderately increased expression of CD21. Gene-expression profiling showed that increased B cell production in IRF8-CKO mice was associated with changes in expression of genes involved in regulation of transcription, signaling, and inflammation. Functional studies showed that IRF8-CKO mice generated normal Ab responses to T-independent and T-dependent Ags. Thus, IRF8 controls the expansion and maturation of MZ and FO B cells but has little effect on B cell function.

IntroductionLocalization and retention of B cells in the marginal zone (MZ) depends on antigenic specificity, 1,2 interactions between integrins and their receptors, 3 and signaling by the lysophospholipid, S1P, through the S1P 1 receptor. 4 Although MZ B cells are considered nonrecirculatory, exposure to cognate Ag or bacterial products causes them to relocalize from the MZ to the splenic white pulp, 4 providing for efficient delivery of captured Ags to follicular dendritic cells. 5 Although no direct evidence links chemokine involvement to MZ B-cell localization and retention, the MZs are strikingly reduced or absent in mice deficient in a series of factors that may act downstream of chemokine receptors. 6 Recent studies, however, showed that transcripts for the chemokine receptor, CXCR7, were expressed at much higher levels by mouse MZ than follicular (FO) B cells. 7-9 CXCR7 has variously been reported to function as the primary receptor and scavenger for CXCL12, 8,10,11 a modulator of CXCR4 activity, or to act directly on different tumor types. 11,12 This prompted us to determine whether CXCR7 and its ligands, CXCL11 and CXCL12, 11,13 might influence MZ B-cell biology by taking advantage of recently developed CXCR7-specific mAbs and small molecule inhibitors. We found that CXCR7 was expressed on MZ but not on FO B cells and that treatment with inhibitors disrupted the normal organization of the MZ, altered MZ B-cell numbers, and increased serum levels of CXCL12, resulting in altered homeostasis of granulocytes. Methods Flow cytometrySplenic single-cell suspensions were blocked with a Fc receptor-blocking mAb, 2.4G2, and stained with fluorochrome-labeled Abs specific for B220, CD19, CD23, CD21, Gr-1, CD3, CD11b, ␣L, ␣4, ␤1, and ␣4␤7 (purchased from BD Biosciences or eBioscience). In some experiments, cells were stained with anti-CXCR7 mAb (11G8; provided by ChemoCentryx) followed by FITC-conjugated secondary Ab. An isotype control Ab was included as a negative control. The cells were analyzed by FACSCalibur or LSRII (BD Biosciences), and the data were analyzed by FlowJo Version 7.5.5 software (TreeStar). Animals, treatment, serum CXCL12, and histologic analysisFVB and B6 mice (2-6 months old) were purchased from The Jackson Laboratory. FVB mice have unusually large MZs, 14 whereas B6 mice are functionally deficient in CXCL11 because of a deletion in the coding sequence. 15 Mice were injected subcutaneously with CXCR7 antagonists CCX754 (100 mg/kg twice daily) or CCX771 (30 mg/kg daily; provided by ChemoCentryx) for 2-7 days. The specificity, half-life, and effect of the inhibitors have been reported previously. 11,16,17 Control mice were injected with equal volumes of vehicles (10% Captisol). The spleens were analyzed by flow cytometry and confocal microscopy, as described previously, with the use of labeled mAb to IgM, metallophilic macrophages (MOMA-1), and marginal sinus epithelial cells (MAdCAM-1). 18 The slides were imaged at 20°C with the use of ϫ10 and ϫ20 oil-immersion lenses on a Leica SP2 4-chanel c...

Innate-like B-1a cells contribute significantly to circulating natural antibodies and mucosal immunity as well as to immunoregulation. Here we show that these classic functions of B-1a cells segregate between two unique subsets defined by expression of plasma cell alloantigen 1 (PC1), also known as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1