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Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model.

Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O - Int J Mol Sci (2015)

Bottom Line: While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition.The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus.Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA. k.alexandropoulos@mssm.edu.

ABSTRACT
Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.

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Schematic representation of T-cell selection and tolerance induction in the thymus. Bone marrow progenitors enter the thymus at the corticomedullary junction (CMJ) and migrate towards the cortex, where they differentiate into immature thymocytes lacking expression of the CD4 and CD8 coreceptors (double-negative 1-4, DN1-4). Upregulation of CD4 and CD8 gives rise to CD4+CD8+ double-positive (DP) thymocytes whose T-cell receptor binds to self-antigens presented by cortical thymic epithelial cells (cTEC). A fraction of DP thymocytes are positively selected and differentiate into CD4+ or CD8+single-positive (SP) T-cells. These migrate to the medulla, where they bind to tissue-restricted antigens (TRA) presented by medullary TECs (mTEC) and whose expression is regulated by Aire [30,31]. Autoreactive T-cells that bind to TRAs with high affinity are negatively selected. SP T-cells with weak affinity for TRAs are allowed to exit the thymus, whereas T-cells with intermediate affinity for TRAs become regulatory T-cells (Treg). mTEC depletion in Traf6∆TEC mice leads to the production of autoreactive T-cells, impaired production of Tregs and peripheral autoimmunity.
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ijms-16-01980-f001: Schematic representation of T-cell selection and tolerance induction in the thymus. Bone marrow progenitors enter the thymus at the corticomedullary junction (CMJ) and migrate towards the cortex, where they differentiate into immature thymocytes lacking expression of the CD4 and CD8 coreceptors (double-negative 1-4, DN1-4). Upregulation of CD4 and CD8 gives rise to CD4+CD8+ double-positive (DP) thymocytes whose T-cell receptor binds to self-antigens presented by cortical thymic epithelial cells (cTEC). A fraction of DP thymocytes are positively selected and differentiate into CD4+ or CD8+single-positive (SP) T-cells. These migrate to the medulla, where they bind to tissue-restricted antigens (TRA) presented by medullary TECs (mTEC) and whose expression is regulated by Aire [30,31]. Autoreactive T-cells that bind to TRAs with high affinity are negatively selected. SP T-cells with weak affinity for TRAs are allowed to exit the thymus, whereas T-cells with intermediate affinity for TRAs become regulatory T-cells (Treg). mTEC depletion in Traf6∆TEC mice leads to the production of autoreactive T-cells, impaired production of Tregs and peripheral autoimmunity.

Mentions: Over the past several years, our research has focused on elucidating the mechanisms that drive T-cell-mediated autoimmunity. Autoimmunity describes the process of an immune response against self, resulting in tissue destruction and, in extreme cases, organ failure. Autoimmune responses involve the activation of the adaptive arm of the immune system with T-lymphocytes playing an especially important role in disease development and progression. T-lymphocytes develop in the thymus from bone marrow precursors, which are subjected to a series of developmental and differentiation steps to become mature T-cells [23,24]. During thymic development, immature T-cells interact with self-antigens expressed by and presented on the surface of thymic stromal cells, namely thymic epithelial cells (TECs) [25]. Based on their localization within the two major compartments of the thymus, the cortex and medulla, TECs are classified as either cortical or medullary TECs (cTECs and mTECs, respectively). cTECs express a variety of self-antigens presented by major histocompatibility complex (MHC) molecules, which determine the diversity of the T-cell repertoire through the process of positive selection. On the other hand, expression of a different set of self-antigens on mTECs generates a self-tolerant T-cell repertoire through the elimination (negative selection) of autoreactive T-cells that bind to medullary self-antigens with high affinity, a process referred to as central tolerance. In addition, self-antigens expressed by mTECs regulate the production of regulatory T-cells (Tregs), which dampen immune responses in peripheral tissues, a process known as peripheral tolerance [25,26,27,28] (Figure 1). Moreover, mTECs serve as a reservoir for unidirectional transfer of self-antigens to other thymic antigen presenting cells (APCs), such as dendritic cells, which, in turn, mediate CD8+ T-cell cross-priming [29].


Medullary thymic epithelial cells and central tolerance in autoimmune hepatitis development: novel perspective from a new mouse model.

Alexandropoulos K, Bonito AJ, Weinstein EG, Herbin O - Int J Mol Sci (2015)

Schematic representation of T-cell selection and tolerance induction in the thymus. Bone marrow progenitors enter the thymus at the corticomedullary junction (CMJ) and migrate towards the cortex, where they differentiate into immature thymocytes lacking expression of the CD4 and CD8 coreceptors (double-negative 1-4, DN1-4). Upregulation of CD4 and CD8 gives rise to CD4+CD8+ double-positive (DP) thymocytes whose T-cell receptor binds to self-antigens presented by cortical thymic epithelial cells (cTEC). A fraction of DP thymocytes are positively selected and differentiate into CD4+ or CD8+single-positive (SP) T-cells. These migrate to the medulla, where they bind to tissue-restricted antigens (TRA) presented by medullary TECs (mTEC) and whose expression is regulated by Aire [30,31]. Autoreactive T-cells that bind to TRAs with high affinity are negatively selected. SP T-cells with weak affinity for TRAs are allowed to exit the thymus, whereas T-cells with intermediate affinity for TRAs become regulatory T-cells (Treg). mTEC depletion in Traf6∆TEC mice leads to the production of autoreactive T-cells, impaired production of Tregs and peripheral autoimmunity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4307344&req=5

ijms-16-01980-f001: Schematic representation of T-cell selection and tolerance induction in the thymus. Bone marrow progenitors enter the thymus at the corticomedullary junction (CMJ) and migrate towards the cortex, where they differentiate into immature thymocytes lacking expression of the CD4 and CD8 coreceptors (double-negative 1-4, DN1-4). Upregulation of CD4 and CD8 gives rise to CD4+CD8+ double-positive (DP) thymocytes whose T-cell receptor binds to self-antigens presented by cortical thymic epithelial cells (cTEC). A fraction of DP thymocytes are positively selected and differentiate into CD4+ or CD8+single-positive (SP) T-cells. These migrate to the medulla, where they bind to tissue-restricted antigens (TRA) presented by medullary TECs (mTEC) and whose expression is regulated by Aire [30,31]. Autoreactive T-cells that bind to TRAs with high affinity are negatively selected. SP T-cells with weak affinity for TRAs are allowed to exit the thymus, whereas T-cells with intermediate affinity for TRAs become regulatory T-cells (Treg). mTEC depletion in Traf6∆TEC mice leads to the production of autoreactive T-cells, impaired production of Tregs and peripheral autoimmunity.
Mentions: Over the past several years, our research has focused on elucidating the mechanisms that drive T-cell-mediated autoimmunity. Autoimmunity describes the process of an immune response against self, resulting in tissue destruction and, in extreme cases, organ failure. Autoimmune responses involve the activation of the adaptive arm of the immune system with T-lymphocytes playing an especially important role in disease development and progression. T-lymphocytes develop in the thymus from bone marrow precursors, which are subjected to a series of developmental and differentiation steps to become mature T-cells [23,24]. During thymic development, immature T-cells interact with self-antigens expressed by and presented on the surface of thymic stromal cells, namely thymic epithelial cells (TECs) [25]. Based on their localization within the two major compartments of the thymus, the cortex and medulla, TECs are classified as either cortical or medullary TECs (cTECs and mTECs, respectively). cTECs express a variety of self-antigens presented by major histocompatibility complex (MHC) molecules, which determine the diversity of the T-cell repertoire through the process of positive selection. On the other hand, expression of a different set of self-antigens on mTECs generates a self-tolerant T-cell repertoire through the elimination (negative selection) of autoreactive T-cells that bind to medullary self-antigens with high affinity, a process referred to as central tolerance. In addition, self-antigens expressed by mTECs regulate the production of regulatory T-cells (Tregs), which dampen immune responses in peripheral tissues, a process known as peripheral tolerance [25,26,27,28] (Figure 1). Moreover, mTECs serve as a reservoir for unidirectional transfer of self-antigens to other thymic antigen presenting cells (APCs), such as dendritic cells, which, in turn, mediate CD8+ T-cell cross-priming [29].

Bottom Line: While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition.The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus.Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine and Clinical Immunology, the Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1089, New York, NY 10029, USA. k.alexandropoulos@mssm.edu.

ABSTRACT
Autoimmune hepatitis (AIH) is an immune-mediated disorder that affects the liver parenchyma. Diagnosis usually occurs at the later stages of the disease, complicating efforts towards understanding the causes of disease development. While animal models are useful for studying the etiology of autoimmune disorders, most of the existing animal models of AIH do not recapitulate the chronic course of the human condition. In addition, approaches to mimic AIH-associated liver inflammation have instead led to liver tolerance, consistent with the high tolerogenic capacity of the liver. Recently, we described a new mouse model that exhibited spontaneous and chronic liver inflammation that recapitulated the known histopathological and immunological parameters of AIH. The approach involved liver-extrinsic genetic engineering that interfered with the induction of T-cell tolerance in the thymus, the very process thought to inhibit AIH induction by liver-specific expression of exogenous antigens. The mutation led to depletion of specialized thymic epithelial cells that present self-antigens and eliminate autoreactive T-cells before they exit the thymus. Based on our findings, which are summarized below, we believe that this mouse model represents a relevant experimental tool towards elucidating the cellular and molecular aspects of AIH development and developing novel therapeutic strategies for treating this disease.

Show MeSH
Related in: MedlinePlus