Thymic Tolerance Induction Research Articles

Mechanisms of immunological tolerance and their dysregulation in rheumatic diseases

The major tasks of the immune system are protection against infectious agents, maintaining homeostasis by recognizing and neutralizing noxious substances from the environment, and monitoring pathological, e.g. neoplastic tissue changes. It accomplishes these tasks through complex interactions of cellular and humoral components of the innate and adaptive immune system. This review article focuses on acentral problem of self versus non-self discrimination in the development of B and Tlymphocytes as carriers of adaptive immunity. During maturation of the lymphocytes in the bone marrow, large repertoires of lymphocyte receptors are randomly generated by somatic recombination, which as awhole have the capability of recognizing any foreign antigen. In order to reduce the implicit risk of autoaggressive immunity that might arise from evolutionary conserved structural motifs in self and foreign antigens, the adaptive immune system must provide redundant mechanisms (clonal deletion, anergy, quiescence and suppression) to eliminate or inactivate lymphocytes expressing highly avid receptors for autoantigens. Thus, the provision of costimulatory signals resulting in areduced activation threshold of potentially autoreactive anergic Tcells through infection, molecular mimicry, disrupted apoptosis regulation, altered "self" by post-translational modification, genetic changes in transcription factors with critical importance for thymic tolerance induction or signaling components of apoptosis can lead to adisruption of self-tolerance and the induction of pathogenic autoimmunity.

Sirtuin 1: A Dilemma in Transplantation.

Sirtuin 1, a member of sirtuin family of histone deacetylase enzymes, has been implicated in a variety of physiologic and pathologic events, including energy metabolism, cell survival, and age-related alterations. In view of the anti-inflammatory properties of sirtuin 1 along with its protective role in ischemia reperfusion injury, it might be considered as contributing to the promotion of transplantation outcome. However, the potential ability of sirtuin 1 to induce malignancies raises some concerns about its overexpression in clinic. Moreover, despite the findings of sirtuin 1 implication in thymic tolerance induction and T regulatory (Treg) cells survival, there is also evidence for its involvement in Treg suppression and in T helper 17 cells differentiation. The identification of sirtuin 1 natural and synthetic activators leads to the proposal of sirtuin 1 as an eligible target for clinical interventions in transplantation. All positive and negative consequences of sirtuin 1 overactivation/overexpression in the allograft should therefore be studied thoroughly. Herein, we summarize previous findings concerning direct and indirect influences of sirtuin 1 manipulation on transplantation.

CCR7 Modulates the Generation of Thymic Regulatory T Cells by Altering the Composition of the Thymic Dendritic Cell Compartment

Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory Tcell (Treg) fate. CCR7 is required for negative selection of auto-reactive thymocytes in the thymic medulla. Here, we describe an unanticipated contribution of CCR7 to intrathymic Treg generation. Ccr7-/- mice have increased Treg cellularity because of a hematopoietic but non-T cell autonomous CCR7 function. CCR7 expression by thymic dendritic cells (DCs) promotes survival of mature Sirpα- DCs. Thus, CCR7 deficiency results in apoptosis of Sirpα- DCs, which is counterbalanced by expansion of immature Sirpα+ DCs that efficiently induce Treg generation. CCR7 deficiency results in enhanced intrathymic generation of Tregs at the neonatal stage and in lymphopenic adults, when Treg differentiation is critical for establishing self-tolerance. Together, these results reveal a complex function for CCR7 in thymic tolerance induction, where CCR7 not only promotes negative selection but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.

CCR7 modulates the generation of thymic regulatory T cells by altering the composition of the thymic dendritic cell compartment

Abstract Upon recognition of auto-antigens, thymocytes are negatively selected or diverted to a regulatory T cell (Treg) fate. Both dendritic cells (DC) and medullary thymic epithelial cells (mTEC) present antigens to tolerize thymocytes. CCR7 guides thymocytes into the medulla, promoting encounters with medullary DC and mTEC. Thus, in the absence of CCR7 negative selection of auto-reactive thymocytes is impaired and autoimmunity ensues. Here we describe an unanticipated, non-thymocyte intrinsic contribution of CCR7 to intrathymic Treg generation. We find that Ccr7−/− mice have increased Treg cellularity, due to a hematopoietic, but non-T cell autonomous function of CCR7. In addition to thymocytes, thymic DC also express CCR7, which promotes survival of Sirpα−DC. Without CCR7, Sirpα−DC are preferentially lost, altering the composition of the conventional thymic DC compartment to favor intrathymic Treg generation. CCR7 deficiency results in enhanced production of thymic Treg at the neonatal stage and in lymphodeficient adults, when Treg generation is most critical for the establishment of self-tolerance. Together these results reveal a more complex function for CCR7 in thymic tolerance induction, in which CCR7 not only promotes negative selection through its effect on thymocyte localization, but also governs intrathymic Treg generation via non-thymocyte intrinsic mechanisms.

Aire regulates the transfer of antigen from mTECs to dendritic cells for induction of thymic tolerance

AbstractTo investigate the role of Aire in thymic selection, we examined the cellular requirements for generation of ovalbumin (OVA)–specific CD4 and CD8 T cells in mice expressing OVA under the control of the rat insulin promoter. Aire deficiency reduced the number of mature single-positive OVA-specific CD4+ or CD8+ T cells in the thymus, independent of OVA expression. Importantly, it also contributed in 2 ways to OVA-dependent negative selection depending on the T-cell type. Aire-dependent negative selection of OVA-specific CD8 T cells correlated with Aire-regulated expression of OVA. By contrast, for OVA-specific CD4 T cells, Aire affected tolerance induction by a mechanism that operated independent of the level of OVA expression, controlling access of antigen presenting cells to medullary thymic epithelial cell (mTEC)–expressed OVA. This study supports the view that one mechanism by which Aire controls thymic negative selection is by regulating the indirect presentation of mTEC-derived antigens by thymic dendritic cells. It also indicates that mTECs can mediate tolerance by direct presentation of Aire-regulated antigens to both CD4 and CD8 T cells.

Induction of thymic tolerance as possibility in prevention of recurrent spontaneous abortion

A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive cells in the thymus and/or inhibition of specific Th 1 cells clones. Deletion process includes two selection mechanisms in which the thymus eliminates unwanted thymocytes are known as positive selection and negative selection. The thymus is an antigenically privileged site, mainly for it is discrete by blood-thymus barrier. Many researches were shown that intrathymic inoculation of any antigen resulted in specific tolerance induction. The embryo/fetus and placenta are an allograft to which the mother must remain immunologically tolerant in order for the fetus to survive. Today, there is much interest focused on the immunology of recurrent spontaneous abortion (RSA). Up to 50% of RSA may be mediated by the immune system via inadequate maternal anti-paternal response. Nature of this maternal–fetal disturbance represents disbalance in Th 1/Th 2 activity. Contra-shift in Th 1/Th 2 activity is the basis for immunotherapy with paternal leukocyte immunization (PLI). PLI induce some kind of peripheral tolerance on embryonic/fetal/trophoblast antigens, but problems of central tolerance are still open. Intrathymic inoculation of fetal or paternal cells (like leukocyte, thymic dendritic cells, trophoblast cells) or paternal set of MHC molecules may cause central specific tolerance and may be a new possibility for immunotherapy in RSA patients.

Failure of blood–thymus barrier as a mechanism of tumor and trophoblast escape

A major process through which the immune system becomes tolerant to self-proteins involves the deletion of self-reactive clones in the thymus, but clonal deletion is not single mechanisms of thymic tolerance. There is now much evidence that intrathymic antigen expression results in anergy induction of T helper type-1 (Th1) clones in the periphery. Blood–thymus barrier is most important structure for prevention of unwanted penetration of antigens into the thymus. Impermeability of the barrier restrain induction of acquired thymic tolerance on unwanted antigens like microbes and tumor cells. Nevertheless, one of most important mechanism of tumor and trophoblast escape is in anergy of Th1 cells and in Th2 cells domination. Many mechanisms are included in disarrangement of Th1/Th2 balance in pregnancy and tumor bearers, but one of possibility is in failure of blood–thymus barrier. Possible consequences of blood–thymus barrier failure are trophoblast-specific or tumor-specific antigens penetrate into the thymus, deletion or anergy of antigen-specific clones and acquired thymic tolerance induction. Blood–thymus barrier is variable structure in anatomical and functional sense so that in certain condition foreign antigens probably can permeate across the barrier. Probability that some factors like hormones, cytokines, prostaglandine and neuromediators can affect blood–thymus barrier permeability and contribute in mechanisms of trophoblast and tumor escape is real but relatively unexplored.

Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity.

It is widely accepted that T cells play an important role in the destruction of beta cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perforin-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP-specific T cell response resulting in rapid development of diabetes. We report here that in perforin-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation of LCMV-GP-specific T cells. Deletion of nu beta 6+ T cells in Mls-1a perforin-deficient mice and the activation of LCMV-GP-specific T cells in perforin-deficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without the development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insulitis but is crucial for the destruction of beta cells in the later phase of the disease process. Other mechanisms or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently induce diabetogenic beta cell damage.

Distinct mechanisms of extrathymic T cell tolerance due to differential expression of self antigen.

Self-reactive T lymphocytes escaping thymic tolerance induction can be rendered non-responsive by contact with antigens in the periphery. In order to determine the parameters controlling peripheral tolerance induction we followed the fate of one well-defined self-reactive T cell population in three different mice expressing the self antigen in various nonlymphoid tissues outside the thymus. This was achieved by crossing anti-Kb T cell receptor (TCR) transgenic mice with transgenic animals expressing the Kb antigen exclusively on hepatocytes or keratinocytes or neuroectodermal cells. Due to this differential expression clonotype+, anti-Kb reactive T cells were found to exist at three different levels of tolerance. These levels were distinct with regard to downregulation of TCR and CD8 molecules, and the requirements for reexpression of TCR in vitro. This differential induction of peripheral tolerance suggest that some tissues are more likely to be affected in autoimmune diseases than others.

T cell activation and thymic tolerance induction require different adhesion intensities of the CD8 co-receptor.

Activation of mature lymphocytes requires in addition to the TCR contact with the corresponding antigen the binding of the CD8 or CD4 co-receptors to MHC class I or class II proteins respectively. To investigate the contribution of the CD8-class I interaction to the elimination of autoreactive T cells during negative selection in the thymus we generated two types of transgenic mice. One set expressed a modified Kb molecule which contained a human HLA-A2 alpha 3 domain, thereby missing the binding residues for the murine CD8 molecules. The second set of mice expressed an anti-Kb specific TCR. Both lines were crossed and in the resulting double transgenic mice the development of Kb-reactive T cells was followed with an anti-clonotypic antibody. Surprisingly, efficient clonal deletion in the thymus was still observed, although the reduced CD8-class I adhesion abrogated effector functions in vivo and in vitro. These results imply that even T cells with intermediate affinity for self are negatively selected in the thymus despite the fact that they are not able to react against self antigens in the periphery. Thus a safety window is created which decreases the risk of autoaggression.