Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment.

Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells.

Ndrg1 is a T-cell clonal anergy factor negatively regulated by CD28 costimulation and interleukin-2.

Induction of T-cell clonal anergy involves serial activation of transcription factors, including NFAT and Egr2/3. However, downstream effector mechanisms of these transcription factors are not fully understood yet. Here we identify Ndrg1 as an anergy factor induced by Egr2.

Specific gut commensal flora locally alters T cell tuning to endogenous ligands.

Differences in gut commensal flora can dramatically influence autoimmune responses, but the mechanisms behind this are still unclear. We report, in a Th1-cell-driven murine model of autoimmune arthritis, that specific gut commensals, such as segmented filamentous bacteria, have the ability to modulate the activation threshold of self-reactive T cells. In the local microenvironment of gut-associated lymphoid tissues, inflammatory cytokines elicited by the commensal flora dynamically enhanced the antigen responsiveness of T cells that were otherwise tuned down to a systemic self-antigen.

Subsets of nonclonal neighboring CD4+ T cells specifically regulate the frequency of individual antigen-reactive T cells.

After an immune response, the expanded population of antigen-specific CD4(+) T cells contract to steady state levels. We have found that the contraction is neither cell-autonomous nor mediated by competition for generic trophic factors, but regulated by relatively rare subsets of neighboring CD4(+) T cells not necessarily of a conventional regulatory T cell lineage. These regulators, referred to as deletors, specifically limit the frequency of particular antigen-specific T cells even though they are not reactive to the same agonist as their targets.

At low precursor frequencies, the T-cell response to chronic self-antigen results in anergy without deletion.

The behavior of self-reactive T cells in the peripheral immune system has often been studied by following the fate of adoptively transferred antigen-specific T cells in antigen expressing mice. In most cases, after a period of expansion, such cells undergo a slow clonal deletion, accompanied by the onset of anergy and/or suppression in the remaining cells. Here, we demonstrate that at initial frequencies approaching those found in normal repertoires, it is possible to completely avoid deletion and still maintain peripheral tolerance.

Development and tolerization of hyperacute rejection in a transgenic mouse graft versus host model.

Background: The hyperacute rejection mediated by preexisting antibodies is a major impediment to the success of transplants across allogeneic and xenogeneic barriers. We report a new mouse model that allows us to not only monitor the sensitization of B cells mediating the hyperacute response but also validate therapeutic strategies for tolerizing them.

Model: The new model system uses 5C.

Historical overview of immunological tolerance.

A fundamental property of the immune system is its ability to mediate self-defense with a minimal amount of collateral damage to the host. The system uses several different mechanisms to achieve this goal, which is collectively referred to as the "process of immunological tolerance." This article provides an introductory historical overview to these various mechanisms, which are discussed in greater detail throughout this collection, and then briefly describes what happens when this process fails, a state referred to as "autoimmunity.

Two-step binding of transcription factors causes sequential chromatin structural changes at the activated IL-2 promoter.

Most gene promoters have multiple binding sequences for many transcription factors, but the contribution of each of these factors to chromatin remodeling is still unclear. Although we previously found a dynamic change in the arrangement of nucleosome arrays at the Il2 promoter during T cell activation, its timing preceded that of a decrease in nucleosome occupancy at the promoter. In this article, we show that the initial nucleosome rearrangement was temporally correlated with the binding of NFAT1 and AP-1 (Fos/Jun), whereas the second step occurred in parallel with the recruitment of other transcription factors and RNA polymerase II.

Impairment of immunological synapse formation in adaptively tolerant T cells.

Adaptive tolerance is a hyporesponsive state in which lymphocyte Ag receptor signaling becomes desensitized after prolonged in vivo encounter with Ag. The molecular mechanisms underlying this hyporesponsive state in T cells are not fully understood, although a major signaling block has been shown to be present at the level of ZAP70 phosphorylation of linker for activation of T cells (LAT). In this study, we investigated the ability of adaptively tolerant mouse T cells to form conjugates with Ag-bearing APCs and to translocate signaling molecules into the interface between the T cells and APCs.

Tbata modulates thymic stromal cell proliferation and thymus function.

Niche availability provided by stromal cells is critical to thymus function. Thymi with diminished function contain fewer stromal cells, whereas thymi with robust function contain proliferating stromal cell populations. Here, we show that the thymus, brain, and testes-associated gene (Tbata; also known as SPATIAL) regulates thymic epithelial cell (TEC) proliferation and thymus size.

Induction of T cell anergy: integration of environmental cues and infectious tolerance.

Anergy is a state of long-term hyporesponsiveness in T cells that is characterized by an active repression of TCR signaling and IL-2 expression [1]. Several forms of anergy have been described and the past few years have brought to light an increasing number of 'anergic factors' involved in the induction and the active maintenance of the state in lymphocytes. The role of mTOR and other related metabolic sensors and regulators has recently emerged as of particular importance in broadening our view of anergy-inducing signals.

A new fractionation assay, based on the size of formaldehyde-crosslinked, mildly sheared chromatin, delineates the chromatin structure at promoter regions.

To explore the higher order structure of transcribable chromatin in vivo, its local configuration was assessed through the accessibility of the chromatin to crosslinking with formaldehyde. The application of crosslinked and mildly sheared chromatin to sedimentation velocity centrifugation followed by size-fractionation of the DNA enabled us to biochemically distinguish between chromatin with heavily versus sparsely crosslinkable structures. The separated fractions showed a good correlation with gene expression profiles.

Themis is a member of a new metazoan gene family and is required for the completion of thymocyte positive selection.

T cell antigen receptor (TCR) signaling in CD4(+)CD8(+) double-positive thymocytes determines cell survival and lineage commitment, but the genetic and molecular basis of this process is poorly defined. To address this issue, we used ethylnitrosourea mutagenesis to identify a previously unknown T lineage-specific gene, Themis, which is critical for the completion of positive selection. Themis contains a tandem repeat of a unique globular domain (called 'CABIT' here) that includes a cysteine motif that defines a family of five uncharacterized vertebrate proteins with orthologs in most animal species.

Biphasic regulation of Il2 transcription in CD4+ T cells: roles for TNF-alpha receptor signaling and chromatin structure.

We describe a novel biphasic regulation of Il2 transcription in naive CD4(+) T cells. Few ( approximately 5%) CD4(+) T cells transcribe Il2 within 6 h of anti-TCR-beta plus anti-CD28 stimulation (early phase). Most naive CD4(+) T cells do not initiate Il2 transcription until after an additional approximately 12 h of T cell stimulation (late phase).

TLR ligands differentially modulate T cell responses to acute and chronic antigen presentation.

The outcome of peripheral T cell activation is thought to be largely determined by the context in which the cognate Ag is initially presented. In this framework, microbial products that can activate APCs via TLRs are considered critical in converting an otherwise tolerogenic context to an immunogenic one. We examine this idea using a model system where naive T cells are stimulated in the periphery by a persistent self Ag.

Molecular mechanisms for adaptive tolerance and other T cell anergy models.

Since the original description of T cell anergy in CD4 clones from mice and humans, a number of different unresponsive states have been described, both in vivo and in vitro, that have been called anergic. While initial attempts were made to understand the similarities between the different models, it has now become clear from biochemical experiments that many of them have different molecular mechanisms underlying their unresponsiveness. In this review we will detail our own work on the in vivo model referred to as adaptive tolerance and then attempt to compare this biochemical state to the multitude of other states that have been described in the literature.

The lymphopenic mouse in immunology: from patron to pariah.

A recent surge of interest in the behavior of T and B cells in lymphopenic model systems has resurrected a certain cynicism about the validity of using such models to answer important immunological questions. Here we discuss this skepticism in a broader historical context.

The impact of T cell intrinsic antigen adaptation on peripheral immune tolerance.

Overlapping roles have been ascribed for T cell anergy, clonal deletion, and regulation in the maintenance of peripheral immunological tolerance. A measurement of the individual and additive impacts of each of these processes on systemic tolerance is often lacking. In this report we have used adoptive transfer strategies to tease out the unique contribution of T cell intrinsic receptor calibration (adaptation) in the maintenance of tolerance to a systemic self-antigen.

Primer: mechanisms of immunologic tolerance.

Successful adaptive immunity against a broad range of pathogens depends on the diversity of randomly generated T-lymphocyte and B-lymphocyte receptors. A subset of these receptors will be self-reactive and must be regulated to prevent autoimmunity. The process of immunologic tolerance addresses this problem by either purging autoreactive receptors from the system or tuning down their reactivity sufficiently to prevent disease.

Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell.

Sprouty (Spry) is known to be a negative feedback inhibitor of growth factor receptor signaling through inhibition of the Ras/MAPK pathway. Several groups, however, have reported a positive role for Spry involving sequestration of the inhibitory protein c-Cbl. Thus, Spry may have various functions in the regulation of receptor-mediated signaling depending on the context.

Adaptive tolerance and clonal anergy are distinct biochemical states.

Adaptive tolerance is a process by which T cells become desensitized when Ag stimulation persists following an initial immune response in vivo. To examine the biochemical changes in TCR signaling present in this state, we used a mouse model in which Rag2(-/-) TCR-transgenic CD4(+) T cells were transferred into CD3epsilon(-/-) recipients expressing their cognate Ag. Compared with naive T cells, adaptively tolerant T cells had normal levels of TCR and slightly increased levels of CD4.

Low-dose radiation plus rapamycin promotes long-term bone marrow chimerism.

Background: The ability to achieve significant donor engraftment without fully myeloablative conditioning has revolutionized allogeneic stem cell transplantation. These nonmyeloablative approaches may allow extension of this potentially curative modality to an increasing number of patients including those with non-malignant diseases. Although a number of regimens have been explored, the optimal means of conditioning has not been determined.

Egr-2 and Egr-3 are negative regulators of T cell activation.

T cell receptor engagement in the absence of proper accessory signals leads to T cell anergy. E3 ligases are involved in maintaining the anergic state. However, the specific molecules responsible for the induction of anergy have yet to be elucidated.

Natural regulatory T cells and self-tolerance.

The adaptive immune system allows individual organisms to mount defensive reactions against unanticipated pathogens by developmentally creating a diverse repertoire of clonally distributed receptors capable of recognizing a multitude of antigens and then expanding as effector cell populations those that can recognize molecules from the pathogens. To function properly, the system must deal with the problem of randomly generated receptors that can recognize self components. Most solutions to this self-tolerance problem are cell intrinsic and involve the deletion or inactivation of autoreactive cells.