Dynamic Changes During the Immune Response in T Cell–Antigen-presenting Cell Clusters Isolated from Lymph Nodes

Activation of antigen-specific T cells by mature dendritic cells in secondary lymphoid organs is a key control point of the adaptive immune response. Here we describe the ex vivo isolation of preformed multicellular clusters between T cells and antigen-presenting cells. Adoptively transferred, antigen-specific T cells segregated into individual clusters where their activation and proliferation was initiated in vivo. Transit of the T cell cohort through the cluster compartment required 32–36 h. The precise timing of the response to agonistic epitopes was remarkably invariant regardless of the T cell lineage, the major histocompatibility complex haplotype, and the antigen dose. Interestingly, initiation of cell division of T cells specific for a subdominant epitope and a weak agonist was delayed by 6 h. The results provide a basis for the analysis of short range, mutual cell–cell interactions within such confined microenvironments

Thymocytes can tolerize thymocytes by clonal deletion in vitro

Clonal deletion of thymocytes bearing TCR for self antigens is one major mechanism of T cell tolerance induction. Peptide antigen-induced deletion of thymocytes from αβ TCR transgenic mice has been studied using single cell suspension cultures. The results show that antigen-presenting immature CD4+CD8+ thymocytes can tolerize antigen-reactive immature thymocytes in vitro by programmed cell death (apoptosis) 6-8 h after antigen exposure. Antigen-induced apoptosis of immature thymocytes was inhibited by antibodies specific for the αβ TCR, CD3, CD8, and LFA-1 molecules. This implies that clonal elimination of self-reactive CD4+CD8+ thymocytes does not depend on specialized deleting cell types in the thymus and occurs whenever the TCR of immature thymocytes bind antigen fragments presented by MHC molecule

Promiscuous gene expression in thymic epithelial cells is regulated at multiple levels

The role of central tolerance induction has recently been revised after the discovery of promiscuous expression of tissue-restricted self-antigens in the thymus. The extent of tissue representation afforded by this mechanism and its cellular and molecular regulation are barely defined. Here we show that medullary thymic epithelial cells (mTECs) are specialized to express a highly diverse set of genes representing essentially all tissues of the body. Most, but not all, of these genes are induced in functionally mature CD80hi mTECs. Although the autoimmune regulator (Aire) is responsible for inducing a large portion of this gene pool, numerous tissue-restricted genes are also up-regulated in mature mTECs in the absence of Aire. Promiscuously expressed genes tend to colocalize in clusters in the genome. Analysis of a particular gene locus revealed expression of clustered genes to be contiguous within such a cluster and to encompass both Aire-dependent and –independent genes. A role for epigenetic regulation is furthermore implied by the selective loss of imprinting of the insulin-like growth factor 2 gene in mTECs. Our data document a remarkable cellular and molecular specialization of the thymic stroma in order to mimic the transcriptome of multiple peripheral tissues and, thus, maximize the scope of central self-tolerance

Information Fusion in the Immune System

Biologically-inspired methods such as evolutionary algorithms and neural networks are proving useful in the field of information fusion. Artificial Immune Systems (AISs) are a biologically-inspired approach which take inspiration from the biological immune system. Interestingly, recent research has show how AISs which use multi-level information sources as input data can be used to build effective algorithms for real time computer intrusion detection. This research is based on biological information fusion mechanisms used by the human immune system and as such might be of interest to the information fusion community. The aim of this paper is to present a summary of some of the biological information fusion mechanisms seen in the human immune system, and of how these mechanisms have been implemented as AISsComment: 10 pages, 6 tables, 6 figures, Information Fusio

Regulation of medullary thymic epithelial cell differentiation and function by the signaling protein Sin

Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma–dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady–state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus

Biphasic Aire expression in early embryos and in medullary thymic epithelial cells before end-stage terminal differentiation

The roles of autoimmune regulator (Aire)–expressing medullary thymic epithelial cells (mTECs) in the organization of the thymic microenvironment for establishing self-tolerance are enigmatic. We sought to monitor the production and maintenance of Aire-expressing mTECs by a fate-mapping strategy in which bacterial artificial chromosome transgenic (Tg) mice expressing Cre recombinase under the control of the Aire regulatory element were crossed with a GFP reporter strain. We found that, in addition to its well recognized expression within mature mTECs, Aire was expressed in the early embryo before emergence of the three germ cell layers. This observation may help to explain the development of ectodermal dystrophy often seen in patients with AIRE deficiency. With the use of one Tg line in which Cre recombinase expression was confined to mTECs, we found that Aire+CD80high mTECs further progressed to an Aire−CD80intermediate stage, suggesting that Aire expression is not constitutive from after its induction until cell death but instead is down-regulated at the beginning of terminal differentiation. We also demonstrated that many mTECs of Aire-expressing lineage are in close contact with thymic dendritic cells. This close proximity may contribute to transfer of tissue-restricted self-antigens expressed by mTECs to professional antigen-presenting cells

Loss of Roquin induces early death and immune deregulation but not autoimmunity

Deletion of Roquin in T or B cells, or in the entire hematopoietic system of mice, alters immune homeostasis but does not result in autoimmunity