Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin αEβ7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. αE −CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, αE-positive subsets (CD25+ and CD25−) displayed an effector/memory phenotype expressing high levels of E/P-selectin–binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, αE-expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

During ageing thymic function declines and is unable to meet the demand for peripheral T helper (Th) cell replenishment. Therefore, population maintenance of naive Th cells must be at least partly peripherally based. Such peripheral postthymic expansion of recent thymic emigrants (RTEs) during ageing consequently should lead to loss or dilution of T cell receptor excision circles (TRECs) from a subset of naive T cells. We have identified two subsets of naive Th cells in human adult peripheral blood characterized by a striking unequal content of TRECs, indicating different peripheral proliferative histories. TRECs are highly enriched in peripheral naive CD45RA+ Th cells coexpressing CD31 compared with peripheral naive CD45RA+ Th cells lacking CD31 expression, in which TRECs can hardly be detected. Furthermore we show that CD31−CD45RA+ Th cells account for increasing percentages of the naive peripheral Th cell pool during ageing but retain phenotypic and functional features of naive Th cells. As CD31 is lost upon T cell receptor (TCR) engagement in vitro, we hypothesize that TCR triggering is a prerequisite for homeostatically driven peripheral postthymic expansion of human naive RTEs. We describe here the identification of peripherally expanded naive Th cells in human adult blood characterized by the loss of CD31 expression and a highly reduced TREC content.

IntroductionCompelling evidence indicates that regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to selfand foreign antigens (Ags). [1][2][3] In mice and humans, various subsets of T lymphocytes that have the ability to down-regulate the proliferation of autoimmune effector cells have been isolated. [4][5][6] CD4 ϩ CD25 ϩ T cells are the most extensively studied Treg cells. Eliminating CD4 ϩ CD25 ϩ T cells from the periphery of mice leads to the development of systemic autoimmune diseases, and adding them back can ameliorate experimentally induced autoimmune diseases and graft-versus-host disease after allogeneic bone marrow transplantation. 7,8 Other Treg cells, including CD4 ϩ CD45Rb low , CD4 ϩ DX5 ϩ T cells, 9 CD8 ϩ T cells, 10 T-cell receptor (TCR)␥␦ ϩ cells, 11 and TCR␣␤ ϩ CD3 ϩ CD4 Ϫ CD8 Ϫ double-negative (DN) T cells 12,13 have also been demonstrated to have a potent role in down-regulating immune responses.The majority of peripheral TCR␣␤ ϩ CD3 ϩ T cells in normal mice express either CD4 or CD8 molecules. However, approximately 1% to 3% of peripheral CD3 ϩ T cells express TCR␣␤ but neither CD4 nor CD8 and are thus DN T cells. Strober et al 14 were the first to describe a natural suppressor activity of DN T cells that was not major histocompatibility complex (MHC) restricted. In humans and mice, DN T cells are detected in lymphoid and nonlymphoid tissues (for a review, see Reimann 15 ). Clonal or oligoclonal expansion of DN T cells in humans has been reported in healthy individuals 16 and in patients with either autoimmune diseases 15,17 or combined immunodeficiency with features of autologous graft-versus-host disease. 18 Zhang and colleagues 12 were the first to identify and characterize Ag-specific DN Treg cells. They initially demonstrated, in mice, that DN Treg cells have a unique phenotype that makes the DN Treg cells different from any previously described T cell. They further demonstrated that (1) DN Treg cells, as a novel subset of Treg cells, can specifically down-regulate immune responses toward allo-Ags both in vitro and in vivo 12 ; (2) both primary activated and cloned DN Treg cells can specifically kill activated CD4 ϩ and CD8 ϩ T cells with the same TCR specificity 12,19,20 ; and (3) infusion of in vitro-activated DN Treg cells leads to significant prolongation of donor-specific skin 12 and heart graft survival. 21 Others have shown that DN Treg cells also play an immune regulatory role in autoimmune and infectious diseases. 13 In vitro studies have identified a unique mechanism by which DN Treg cells mediate an Ag-specific suppression of syngeneic responder cells. Studies showed that DN Treg cells can use their TCR to acquire allo-MHC peptides from antigen-presenting cells (APCs) and use them to specifically trap and kill CD4 ϩ or CD8 ϩ T cells that recognize the same allo-MHC peptides through a process that requires cell-to-cell contact and Fas/FasL interaction. 12 Although it has been evident that the DN Treg cell population constitutes a unique li...

By using an animal model that addressed the clinical phenomenon of diameter discrepancy between vein graft and bypassed artery, we could demonstrate that suppression of intimal hyperplasia required constrictive mesh sizes.

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The B-cell chronic lymphocytic leukemia (CLL)/lymphoma 11B gene (BCL11B) encodes a Kru¨ppel-like zincfinger protein, which plays a crucial role in thymopoiesis and has been associated with hematopoietic malignancies. It was hypothesized that BCL11B may act as a tumorsuppressor gene, but its precise function has not yet been elucidated. Here, we demonstrate that the survival of human T-cell leukemia and lymphoma cell lines is critically dependent on Bcl11b. Suppression of Bcl11b by RNA interference selectively induced apoptosis in transformed T cells whereas normal mature T cells remained unaffected. The apoptosis was effected by simultaneous activation of death receptor-mediated and intrinsic apoptotic pathways, most likely as a result of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) upregulation and suppression of the Bcl-xL antiapoptotic protein. Our data indicate an antiapoptotic function of Bcl11b. The resistance of normal mature T lymphocytes to Bcl11b suppression-induced apoptosis and restricted expression pattern make it an attractive therapeutic target in T-cell malignancies.

Compelling evidence indicate that regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to self and foreign antigens (Ag). Various subsets of T lymphocytes have been isolated in mice and humans that have the ability to down-regulate the proliferation of autoimmune effector cells. Recently, a novel subset of Ag-specific T-cell receptor (TCR)αβ+ CD4−CD8− (double negative, DN) Treg cells has been found to be able to prevent the rejection of skin and heart allografts by specifically inhibiting the function of anti-graft-specific CD8+ T cells. Here we demonstrate that peripheral DN Treg cells are present in humans, where they constitute about 1% of total CD3+ T cells, and consist of both naïve and Ag-experienced cells. Furthermore, analysis of T-cell receptor excision circles (TRECs) indicate that DN T cells are not recent thymic emigrants, but rather an expanded T-cell subset. MHC multimer staining revelaed a distinct population of DN T cells recognizing common MHC class I-restricted CMV and EBV antigens. DN T cells exhibited a strong proliferative response upon stimulation with allogeneic antigen presenting cells (APC) and secreted high amounts of IFN-γ but no IL-2, with some IL-5, and marginal levels of IL-4 and IL-10. Similar to murine DN Treg cells, human DN Treg cells are able to acquire peptide-HLA-A2 complexes from APCs by cell contact-dependent mechanisms. Furthermore, such acquired peptide-HLA complexes appear to be functionally active, in that CD8+ T cells specific for the HLA-A2-restricted self peptide, Melan-A, became sensitive to apoptosis by neighboring DN T cells after acquisition of Melan-A-HLA-A2 complexes and revealed a reduced proliferative response. These results demonstrate for the first time that a sizeable population of peripheral DN Treg cells exists in humans that are able to suppress Ag-specific T cells. DN Treg cells may serve to limit clonal expansion of allo-Ag-specific T cells after transplantation.

The t(11;14)(p13;q11) is presumed to arise from an erroneous T-cell receptor delta TCRD V(D)J recombination and to result in LMO2 activation. However, the mechanisms underlying this translocation and the resulting LMO2 activation are poorly defined. We performed combined in vivo, ex vivo, and in silico analyses on 9 new t(11;14)(p13;q11)-positive T-cell acute lymphoblastic leukemia (T-ALL) as well as normal thymocytes.Our data support the involvement of 2 distinct t(11;14)(p13;q11) V(D)J-related translocation mechanisms. We provide compelling evidence that removal of a negative regulatory element from the LMO2 locus, rather than juxtaposition to the TCRD enhancer, is the main determinant for LMO2 activation in the majority of t(11;14)(p13;q11) translocations. Furthermore, the position of the LMO2 breakpoints in T-ALL in the light of the occurrence of TCRD-LMO2 translocations in normal thymocytes points to a critical role for the exact breakpoint location in determining LMO2 activation levels and the consequent pressure for T-ALL development. IntroductionThe t(11,14)(p13;q11) (LMO2-TCRD) occurs frequently (7%) and is considered a paradigm for T-cell receptor (TCR)-associated translocations in human T-cell acute lymphoblastic leukemia (T-ALL). 1,2 Although the causative mechanism is still poorly understood, it is generally assumed to result from erroneous V(D)J recombination during T-cell development. 3 So far only 5 t(11;14)(p13;q11) junctions have been sequenced. [4][5][6][7][8][9] In 3 cases, cryptic sequences resembling TCR/Ig recombination signal sequences (RSSs) were located next to the LMO2 breakpoint. Two of these concerned the same cryptic RSS (cRSS). Consequently, RAG mistargeting of an LMO2 cRSS at the moment of TCRD recombination was proposed as the causal mechanism. [4][5][6][7] Recently, we and others demonstrated that this shared LMO2 cRSS could indeed function as target for V(D)J recombination in ex vivo recombination assays. 10,11 Although these data fit with illegitimate V(D)J recombination due to RAG mistargeting, they are clearly too limited to draw firm conclusions regarding recurrent involvement of this mechanism in t(11;14)(p13;q11). Dogmatically, TCR-associated translocations are believed to result in protooncogene activation due to juxtaposition to a TCR enhancer or other regulatory elements. 1,12 LMO2 consists of 6 exons and is transcribed from 2 promoters, a distal promoter upstream of exon 1 and a proximal promoter upstream of exon 3, with both transcripts encoding the same protein. 13 Strikingly, our retrospective analysis of published t(11;14)(p13;q11) translocation junctions 4-8 revealed no juxtaposition of LMO2-coding exons to the TCRD enhancer, suggesting alternative LMO2 activation mechanisms. Distal promoter/negative regulatory element (NRE) removal has been suggested as an LMO2 activation mechanism in t(11;14)(p13;q11) 13,14 but this has never been shown experimentally.Clearly, many issues regarding how t(11;14)(p13;q11) leads to LMO2 activation and T-ALL are so far poorly unde...