Functional Roles of the IgM Fc Receptor in the Immune System

It is now evident from studies of mice unable to secrete IgM that both non-immune “natural” and antigen-induced “immune” IgM are important for protection against pathogens and for regulation of immune responses to self-antigens. Since identification of its Fc receptor (FcμR) by a functional cloning strategy in 2009, the roles of FcμR in these IgM effector functions have begun to be explored. Unlike Fc receptors for switched Ig isotypes (e.g., FcγRs, FcεRs, FcαR, Fcα/μR, pIgR, FcRn), FcμR is selectively expressed by lymphocytes: B, T, and NK cells in humans and only B cells in mice. FcμR may have dual signaling ability: one through a potential as yet unidentified adaptor protein non-covalently associating with the FcμR ligand-binding chain via a His in transmembrane segment and the other through its own Tyr and Ser residues in the cytoplasmic tail. FcμR binds pentameric and hexameric IgM with a high avidity of ~10 nM in solution, but more efficiently binds IgM when it is attached to a membrane component via its Fab region on the same cell surface (cis engagement). Four different laboratories have generated Fcmr-ablated mice and eight different groups of investigators have examined the resultant phenotypes. There have been some clear discrepancies reported that appear to be due to factors including differences in the exons of Fcmr that were targeted to generate the knockouts. One common feature among these different mutant mice, however, is their propensity to produce autoantibodies of both IgM and IgG isotypes. In this review, we briefly describe recent findings concerning the functions of FcμR in both mice and humans and propose a model for how FcμR plays a regulatory role in B cell tolerance

HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Regulatory T cells: roles of T cell receptor for their development and function

Naturally arising CD4(+)CD25(+) regulatory T cells (Treg cells), which specifically express the forkhead family transcription factor Foxp3, are essential for the maintenance of immunological self-tolerance and immune homeostasis. Stimulation of the T cell antigen receptor (TCR) via recognizing self-peptide/major histocompatibility complex (MHC) is required for their expression of Foxp3 in the course of their development in the thymus. The TCR repertoires displayed by Treg cells and naïve T cells are apparently distinct, suggesting that Treg cells with high reactivity to self-peptide/MHC ligands are somehow driven to Treg cell lineage in the thymus. Treg cells also require stimulation via TCR to exert suppression in the periphery. At the molecular level, assembly of Foxp3, Foxp3-interacting factors, and chromatin-remodeling factors is in part under the control of TCR signaling, and TCR stimulation alters Foxp3-dependent transcriptional regulation, protein-protein interaction, and Foxp3 recruitment to the specific genomic loci. These findings collectively indicate that the TCR signaling is essential for suppressive function of Treg cells and that TCR has a determinant role for driving developing T cells to the Foxp3(+)CD4(+)CD25(+) Treg cell lineage and differentiation

Menin Missense Mutants Associated with Multiple Endocrine Neoplasia Type 1 Are Rapidly Degraded via the Ubiquitin-Proteasome Pathway

MEN1 is a tumor suppressor gene that is responsible for multiple endocrine neoplasia type 1 (MEN1) and that encodes a 610-amino-acid protein, called menin. While the majority of germ line mutations identified in MEN1 patients are frameshift and nonsense mutations resulting in truncation of the menin protein, various missense mutations have been identified whose effects on menin activity are unclear. For this study, we analyzed a series of menin proteins with single amino acid alterations and found that all of the MEN1-causing missense mutations tested led to greatly diminished levels of the affected proteins in comparison with wild-type and benign polymorphic menin protein levels. We demonstrate here that the reduced levels of the mutant proteins are due to rapid degradation via the ubiquitin-proteasome pathway. Furthermore, the mutants, but not wild-type menin, interact both with the molecular chaperone Hsp70 and with the Hsp70-associated ubiquitin ligase CHIP, and the overexpression of CHIP promotes the ubiquitination of the menin mutants in vivo. These findings reveal that MEN1-causing missense mutations lead to a loss of function of menin due to enhanced proteolytic degradation, which may be a common mechanism for inactivating tumor suppressor gene products in familial cancer