Foxp3+ regulatory T cells are activated in spite of B7‐CD28 and CD40‐CD40L blockade

Costimulatory signals are required for priming and activation of naive T cells, while it is less clear how they contribute to induction of regulatory T (Treg)‐cell activity. We previously reported that the blockade of the B7‐CD28 and CD40L‐CD40 interaction efficiently suppresses allogeneic T‐cell activation in vivo. This was characterized by an initial rise in Foxp3⁺ cells, followed by depletion of host‐reactive T cells. To further investigate effects of costimulatory blockade on Treg cells, we used an in vitro model of allogeneic CD4⁺ cell activation. When CTLA‐4Ig and anti‐CD40L mAb (MR1) were added to the cultures, T‐cell proliferation and IL‐2 production were strongly reduced. However, Foxp3⁺ cells proliferated and acquired suppressive activity. They suppressed activation of syngeneic CD4⁺ cells much more efficiently than did freshly isolated Treg cells. CD4⁺ cells activated by allogeneic cells in the presence of MR1 and CTLA‐4Ig were hyporesponsive on restimulation, but their response was restored to that of naive CD4⁺ cells when Foxp3⁺ Treg cells were removed. We conclude that natural Treg cells are less dependent on B7‐CD28 or CD40‐CD40L costimulation compared with Foxp3^? T cells. Reduced costimulation therefore alters the balance between Teff and Treg‐cell activation in favor of Treg‐cell activity.     

Composition of the HLA‐DR‐associated human thymus peptidome

Major histocompatibility complex class II (MHC‐II) molecules bind to and display antigenic peptides on the surface of antigen‐presenting cells (APCs). In the absence of infection, MHC‐II molecules on APCs present self‐peptides and interact with CD4⁺ T cells to maintain tolerance and homeostasis. In the thymus, self‐peptides bind to MHC‐II molecules expressed by defined populations of APCs specialised for the different steps of T‐cell selection. Cortical epithelial cells present peptides for positive selection, whereas medullary epithelial cells and dendritic cells are responsible for peptide presentation for negative selection. However, few data are available on the peptides presented by MHC molecules in the thymus. Here, we apply mass spectrometry to analyse and identify MHC‐II‐associated peptides from five fresh human thymus samples. The data show a diverse self‐peptide repertoire, mostly consisting of predicted MHC‐II high binders. Despite technical limitations preventing single cell population analyses of peptides, these data constitute the first direct assessment of the HLA‐II‐bound peptidome and provide insight into how this peptidome is generated and how it drives T‐cell repertoire formation.     

Peripheral CD4+ T‐cell tolerance is induced in vivo by rare antigen‐bearing B cells in follicular,marginal zone,and B‐1 subsets

B cells are efficient APCs when they internalize antigen via BCR‐mediated uptake. Adoptively transferred antigen‐presenting B cells can induce T‐cell tolerance to foreign and self antigens; however, it is unknown whether endogenous B cells presenting self‐peptides interact with naïve T cells and contribute to peripheral T‐cell self‐tolerance. Moreover, the relative abilities of mature B‐cell subsets to induce T‐cell tolerance have not been examined. To address these questions, we created a new mouse model wherein a very small fraction of B cells expresses an antigen transgene that cannot be transferred to other APCs. We limited antigen expression to follicular, marginal zone, or B‐1 B‐cell subsets and found that small numbers of each subset interacted with naïve antigen‐specific T cells. Although antigen expressed by B‐1 B cells induced the most T‐cell division, divided T cells subsequently disappeared from secondary lymphoid tissues. Independent of which B‐cell subset presented antigen, the remaining T cells were rendered hypo‐responsive, and this effect was not associated with Foxp3 expression. Our data show that physiologically relevant proportions of B cells can mediate peripheral T‐cell tolerance, and suggest that the mechanisms of tolerance induction might differ among follicular, marginal zone, and B‐1 B‐cell subsets.     

Insulin Administration Confers Diabetes-Preventive Properties to NOD Mice Derived Dendritic Cells

Administration of autoantigen can be of value for prevention of autoimmune diabetes and it has been speculated that the control point of dendritic cells (DC) for the induction of peripheral tolerance may be highly relevant. We examined the properties of DC associated with immune suppression in NOD mice by insulin injection subcutaneously and the ability of which to suppress diabetes transfer by diabetogenic effector cells in secondary NOD-SCID recipients. Our data showed that the surface expressions of MHC II and CD86 on NOD-derived DC were increased after insulin treatment compared with those on PBS controlled mice. The dendritic cells with a mature phenotype and increased MLR stimulation adoptively transferred immune tolerogenic effects in secondary NOD-SCID mice, which were associated with significant greater IL-10, TGF-β production and CD4⁺CD25⁺T differentiation from splenocytes compared with NOD-SCID control recipients. Moreover, treatment with DC remarkably decreased the incidence of diabetes in secondary recipients. These results suggest that a subtype of DC generated by insulin subcutaneous treated NOD mice confers potential protection from diabetes through polarizing the immune response towards a Th2 regulatory pathway.     

Promotion and prevention of autoimmune disease by CD8+ T cells

Until recently, little was known about the importance of CD8+ T effectors in promoting and preventing autoimmune disease development. CD8+ T cells can oppose or promote autoimmune disease through activities as suppressor cells and as cytotoxic effectors. Studies in several distinct autoimmune models and data from patient samples are beginning to establish the importance of CD8+ T cells in these diseases and to define the mechanisms by which these cells influence autoimmunity. CD8+ effectors can promote disease via dysregulated secretion of inflammatory cytokines, skewed differentiation profiles and inappropriate apoptosis induction of target cells, and work to block disease by eliminating self-reactive cells and self-antigen sources, or as regulatory T cells. Defining the often major contribution of CD8+ T cells to autoimmune disease and identifying the mechanisms by which they alter the pathogenesis of disease is a rapidly expanding area of study and will add valuable information to our understanding of the kinetics, pathology and biology of autoimmune disease.     

Trophoblast Immune Receptors in Maternal-Fetal Tolerance

During pregnancy, interactions between maternal immune cells and fetal trophoblast cells of the placenta would seemingly lead to disaster, as the trophoblast cells are semi-allogeneic and should trigger rejection by the maternal immune response. A fundamental immunologic question of pregnancy as posed by Sir Peter Medawar centers on how immunologic disaster is averted. It is becoming clear that many different mechanisms act during gestation to render the maternal immune system tolerant of the fetus. These include, among others, restricted major histocompatibility complex (MHC) protein expression, the presence of immunosuppressive B7 family members, immunomodulatory adhesion molecules, the expression of apoptosis-inducing proteins, and complement regulatory proteins. Understanding of maternal-fetal tolerance has clinically important implications for the fields of reproduction, autoimmunity and transplantation. Herein are discussed mechanisms by which trophoblast cells are protected from maternal immune cell attack. Specifically the role of trophoblast cell surface proteins at the maternal-fetal interface is considered.     

Molecular and Cellular Mechanisms RegulatingTand B Cell Apoptosis through Fas/FasL Interaction

Fas (CD95) and Fas ligand (FasL) are a receptor/ligand pair critically involved in lymphocyte homeostasis and peripheral tolerance such that genetic defect in either Fas or FasL results in an autoimmune lymphoproliferative syndrome. Fas is a type I transmembrane protein and a member of the tumor necrosis factor receptor (TNFR) family whereas FasL is a type II transmembrane protein and a member of TNF family. Binding of Fas by FasL induces apoptosis of the Fas-expressing cells. In the past few years. Fas/FasL interaction has been connected to a series of important phenomena previously viewed as independent immune processes. The activation-induced T cell death (AICD) and the FasL-mediated cytotoxicity by activated T cells are two critical mechanisms that can account for most of these phenomena. It is in the context of the two mechanisms that we discuss in this review the molecular and cellular events that occur during T/T and T/B interactions that account for the down-regulation of the immune response. We have also discussed recent advances in the areas of FasL gene regulation, lymphokine regulation of AICD, and regulation of B cell susceptibility to FasL. Investigation in these areas should help elucidate the role of Fas/FasL in the complex network of regulatory mechanisms that control immune response and autoimmunity.     

单中心327例次腹膜透析相关性腹膜炎致病菌及药敏结果分析

目的 探讨持续性非卧床腹膜透析(continuous ambulatory peritoneal dialysis,CAPD)相关性腹膜炎的致病菌及其耐药性.方法 回顾性分析2008年1月至2013年5月在我中心就诊的180例327例次CAPD相关性腹膜炎的致病菌及其耐药性.结果 202例次培养阳性,培养阳性率为61.77％.革兰阳性球菌154例次,其中金黄色葡萄球菌及凝固酶阴性葡萄球菌123例次,占病原微生物培养阳性的60.89％;革兰阴性杆菌38例次,其中大肠埃希菌11例次,占病原微生物培养阳性的5.45％;真菌10例次,其中假丝酵母菌7例次,占病原微生物培养阳性的3.47％.革兰阳性球菌对万古霉素耐药率最低,为3.25％,其次为莫西沙星,为5.19％,对利福平、庆大霉素、左氧氟沙星耐药率分别为12.99％、35.71％、45.45％,对青霉素的耐药率最高,达84.42％.革兰阴性菌对哌拉西林/他唑巴坦耐药率最低,为10.53％,其次为头孢他啶,为23.68％,对左氧氟沙星、头孢匹美、庆大霉素耐药率分别为26.32％、28.21％、36.84％,对氨苄西林/舒巴坦的耐药率最高,达50.00％.重复感染54例,共114例次,72例次培养阳性,阳性率为63.16％,其中革兰阳性球菌63例次,占87.50％,革兰阴性杆菌9例次,占12.50％,革兰阳性球菌以金黄色葡萄球菌为主,革兰阴性杆菌以大肠埃希菌为主.结论 本中心CAPD相关性腹膜炎致病菌以革兰阳性球菌为多,接触污染是导致腹膜炎的主要原因.革兰阳性球菌对青霉素耐药率最高,革兰阴性杆菌对氨苄西林/舒巴坦耐药率最高.