We propose a novel role for interleukin (IL) 6 in inducing rapid spontaneous proliferation (SP) of naive CD8 + T cells, which is a crucial step in the differentiation of colitogenic CD8 + T cells. Homeostasis of T cells is regulated by two distinct modes of cell proliferation: major histocompatibility complex/antigen -driven rapid SP and IL-7/IL-15 -dependent slow homeostatic proliferation. Using our novel model of CD8 + T cell -dependent colitis, we found that SP of naive CD8 + T cells is essential for inducing pathogenic cytokine-producing effector T cells. The rapid SP was predominantly induced in mesenteric lymph nodes (LNs) but not in peripheral LNs under the infl uence of intestinal fl ora and IL-6. Indeed, this SP was markedly inhibited by treatment with anti -IL-6 receptor monoclonal antibody (IL-6R mAb) or antibiotic-induced fl ora depletion, but not by anti -IL-7R mAb and/or in IL-15 -defi cient conditions. Concomitantly with the inhibition of SP, anti -IL-6R mAb signifi cantly inhibited the induction of CD8 + T cell -dependent autoimmune colitis. Notably, the transfer of naive CD8 + T cells derived from IL-17 ؊ / ؊ mice did not induce autoimmune colitis. Thus, we conclude that IL-6 signaling is crucial for SP under lymphopenic conditions, which subsequently caused severe IL-17 -producing CD8 + T cell -mediated autoimmune colitis. We suggest that anti -IL-6R mAb may become a promising strategy for the therapy of colitis.

H60, originally described as a dominant minor histocompatibility Ag, is an MHC class I-like molecule that serves as a ligand for the NKG2D receptor. In the present study, we identified two novel mouse chromosome 10-encoded NKG2D ligands structurally resembling H60. These ligands, which we named H60b and H60c, encode MHC class I-like molecules with two extracellular domains. Whereas H60b has a transmembrane region, H60c is a GPI-anchored protein. Recombinant soluble H60b and H60c proteins bound to NKG2D with affinities typical of cell–cell recognition receptors (Kd = 310 nM for H60b and Kd = 8.7 μM for H60c). Furthermore, expression of H60b or H60c rendered Ba/F3 cells susceptible to lysis by NK cells, thereby establishing H60b and H60c as functional ligands for NKG2D. H60b and H60c transcripts were detected only at low levels in tissues of healthy adult mice. Whereas H60b transcripts were detectable in various tissues, H60c transcripts were detected mainly in the skin. Infection of mouse embryonic fibroblasts with murine cytomegalovirus induced expression of H60b, but not H60c or the previously known H60 gene, indicating that transcriptional activation of the three types of H60 genes is differentially regulated. The present study adds two new members to the current list of NKG2D ligands.

Jawless vertebrates such as lamprey and hagfish lack T-cell and Bcell receptors; instead, they have unique antigen receptors known as variable lymphocyte receptors (VLRs). VLRs generate diversity by recombining highly diverse leucine-rich repeat modules and are expressed clonally on lymphocyte-like cells (LLCs). Thus far, two types of receptors, VLRA and VLRB, have been identified in lampreys and hagfish. Recent evidence indicates that VLRA and VLRB are expressed on distinct populations of LLCs that resemble T cells and B cells of jawed vertebrates, respectively. Here we identified a third VLR, designated VLRC, in the lamprey. None of the ≈100 VLRC cDNA clones subjected to sequencing had an identical sequence, indicating that VLRC can generate sufficient diversity to function as antigen receptors. Notably, the C-terminal cap of VLRC exhibits only limited diversity and has important structural differences relative to VLRA and VLRB. Single-cell PCR analysis identified LLCs that rearranged VLRC but not VLRA or VLRB, suggesting the presence of a unique population of LLCs that express only VLRC.antigen receptors | immune system evolution | jawless vertebrates | leucine-rich repeats | somatic rearrangement

Studies using adherent cell lines have shown that glucose transporter-1 (GLUT-1) can function as a receptor for human T-cell leukemia virus type 1 (HTLV). In primary CD4؉ T cells, heparan sulfate proteoglycans (HSPGs) are required for efficient entry of HTLV-1. Here, the roles of HSPGs and GLUT-1 in HTLV-1 and HTLV-2 Env-mediated binding and entry into primary T cells were studied. Examination of the cell surface of activated primary T cells revealed that CD4 ؉ T cells, the primary target of HTLV-1, expressed significantly higher levels of HSPGs than CD8 ؉ T cells. Conversely, CD8 ؉ T cells, the primary target of HTLV-2, expressed GLUT-1 at dramatically higher levels than CD4 ؉ T cells. Under these conditions, the HTLV-2 surface glycoprotein (SU) binding and viral entry were markedly higher on CD8؉ T cells while HTLV-1 SU binding and viral entry were higher on CD4 ؉ T cells. Binding studies with HTLV-1/HTLV-2 SU recombinants showed that preferential binding to CD4 ؉ T cells expressing high levels of HSPGs mapped to the C-terminal portion of SU. Transfection studies revealed that overexpression of GLUT-1 in CD4 ؉ T cells increased HTLV-2 entry, while expression of HSPGs on CD8 ؉ T cells increased entry of HTLV-1. These studies demonstrate that HTLV-1 and HTLV-2 differ in their T-cell entry requirements and suggest that the differences in the in vitro cellular tropism for transformation and in vivo pathobiology of these viruses reflect different interactions between their Env proteins and molecules on CD4؉ and CD8 ؉ T cells involved in entry.Human T-cell leukemia virus type 1 (HTLV-1) and type 2 (HTLV-2) are deltaretroviruses with similar genome structure and an overall nucleotide homology of approximately 70% (reviewed in reference 11). However, the two viruses differ in their pathobiology. HTLV-1 is the causal agent of adult T-cell leukemia and a progressive neurological disorder called HTLV-1-associated myelopathy/tropical spastic paraparesis (12,34,54). In contrast, HTLV-2 is essentially nonpathogenic, although a few cases of neurological disease in HTLV-2-infected individuals have been reported.Entry of retroviruses into target cells involves interactions between the viral envelope (Env) glycoproteins, a surface glycoprotein (SU), and a transmembrane glycoprotein (TM), and specific cell surface molecules referred to as receptors. The SU protein is involved in receptor recognition, and the TM protein triggers the fusion of the viral and cellular membranes, allowing entry of viral particles. For some retroviruses such as ecotropic murine leukemia viruses, a single molecule is sufficient for attachment and entry; for others such as human immunodeficiency virus (HIV), multiple molecules are required (37).Studies of viral interference indicate that HTLV-1, HTLV-2, and related simian viruses share a receptor (46,47). Cells from a variety of species express molecules capable of supporting HTLV-1 Env-mediated fusion. Many, but not all, cell lines can be transduced by HTLV-1 Env-pseudotyped vectors and/or can fuse wit...

Forkhead box (Fox)/winged-helix transcription factors regulate multiple aspects of immune responsiveness and Foxp3 is recognized as an essential functional marker of regulatory T cells. Herein we describe downstream signaling pathways targeted by Foxp3 that may negatively impact retroviral pathogenesis. Overexpression of Foxp3 in HEK 293T and purified CD4+ T cells resulted in a dose-dependent and time-dependent decrease in basal levels of nuclear factor-κB (NF-κB) activation. Deletion of the carboxyl-terminal forkhead (FKH) domain, critical for nuclear localization and DNA-binding activity, abrogated the ability of Foxp3 to suppress NF-κB activity in HEK 293T cells, but not in Jurkat or primary human CD4+ T cells. We further demonstrate that Foxp3 suppressed the transcription of two human retroviral promoters (HIV-1 and human T cell lymphotropic virus type I [HTLV-I]) utilizing NF-κB-dependent and NF-κB-independent mechanisms. Examination of the latter identified the cAMP-responsive element binding protein (CREB) pathway as a target of Foxp3. Finally, comparison of the percent Foxp3+CD4+CD25+ T cells to the HTLV-I proviral load in HTLV-I-infected asymptomatic carriers and patients with HTLV-I-associated myelopathy/tropical spastic paraparesis suggested that high Foxp3 expression is associated with low proviral load and absence of disease. These results suggest an expanded role for Foxp3 in regulating NF-κB- and CREB-dependent cellular and viral gene expression.

The ubiquitin-proteasome pathway, which degrades intracellular proteins, is involved in numerous cellular processes, including the supply of immunocompetent peptides to the antigen presenting machinery. Proteolysis by proteasomes is conducted by three ␤ subunits, ␤1, ␤2, and ␤5, of the 20S proteasome. Recently, a novel ␤ subunit expressed exclusively in cortical thymic epithelial cells was discovered in mice. This subunit, designated ␤5t, is a component of the thymoproteasome, a specialized type of proteasomes implicated in thymic positive selection. In this study, we show that, like its mouse counterpart, human ␤5t is expressed exclusively in the thymic cortex. Human ␤5t was expressed in approximately 80% of cortical thymic epithelial cells and some cortical dendritic cells. Human ␤5t was incorporated into proteasomes with two other catalytically active ␤ subunits ␤1i and ␤2i, forming 20S proteasomes with subunit compositions characteristic of thymoproteasomes. The present study demonstrates, for the first time, the existence of thymoproteasomes in the human thymic cortex, indicating that thymoproteasome function is likely conserved between humans and mice. (Blood. 2009; 113:5186-5191)

We reviewed five cases of sclerosing perineurial tumor of the hand. Four patients were male and one was female with ages ranging from 11 years to 49 years (mean 26 years). The predominant reason for consultation at the outpatient clinic was a slowly growing painless mass. The sites of involvement were the thumb in two cases, and the ring finger, middle finger and palm in one case each. The lesions were hard and firm, well-circumscribed white masses with a fibrous consistency ranging from 1.2 cm to 4.0 cm (mean 2.5 cm) in maximum dimension. Microscopically, all the tumors were composed of thick collagen and variable numbers of small, epithelioid cells exhibiting corded, trabecular and whorled growth patterns. Electron microscopy showed long cytoplasmic processes with a discontinuous basal lamina and occasional pinocytotic vesicles in the tumor cells. Immunohistochemically, most of the tumor cells were positive for epithelial membrane antigen, vimentin, collagen type IV and CD10, but not for S-100 protein, CD34, desmin and cytokeratin. We also observed that the tumor cells were positive for the human erythrocyte glucose transporter (GLUT1) antigen, suggesting that GLUT1 may be a useful marker for the identification of sclerosing perineurioma.

The Foxp3 protein is a specific marker of CD4(+)CD25(+) regulatory T (T(reg)) cells, and its expression is critical to their development and function. Several studies have demonstrated the dysregulation of Foxp3 expression during human inflammatory diseases. Infection with human T lymphotropic virus type 1 (HTLV-1) is associated with the development of a number of inflammatory conditions, including myelopathy, although the majority of individuals who are infected with HTLV-1 remain asymptomatic. To examine the role played by T(reg) cells in the development of inflammatory disease during HTLV-1 infection, we examined Foxp3 expression by flow cytometry. Our analysis showed that HTLV-1-associated myelopathy/tropical spastic paraparesis was associated with a lower expression (compared with that in asymptomatic HTLV-1 carriers and healthy donors) of Foxp3 in peripheral-blood leukocytes. In individuals infected with HTLV-1, Foxp3 expression was inversely correlated with HTLV-1 tax proviral DNA load. These results suggest that impaired Foxp3 expression may contribute to the development of inflammatory disease during HTLV-1 infection.