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The Contribution of Chemokines and Migration to the Induction of Central Tolerance in the Thymus.

Hu Z, Lancaster JN, Ehrlich LI - Front Immunol (2015)

Bottom Line: As T cells develop, they migrate throughout the thymus where they undergo essential bi-directional signaling with stromal cells in distinct thymic microenvironments.Antigen-presenting cells (APCs) within the cortex and medulla display peptides derived from a wide array of self-proteins, which promote thymocyte self-tolerance.Chemokines and adhesion molecules play an essential role in tolerance induction, as they promote migration of developing thymocytes through the different thymic microenvironments and enhance interactions with APCs displaying self-antigens.

View Article: PubMed Central - PubMed

Affiliation: Ehrlich Laboratory, Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin , Austin, TX , USA.

ABSTRACT
As T cells develop, they migrate throughout the thymus where they undergo essential bi-directional signaling with stromal cells in distinct thymic microenvironments. Immature thymocyte progenitors are located in the thymic cortex. Following T cell receptor expression and positive selection, thymocytes undergo a dramatic transition: they become rapidly motile and relocate to the thymic medulla. Antigen-presenting cells (APCs) within the cortex and medulla display peptides derived from a wide array of self-proteins, which promote thymocyte self-tolerance. If a thymocyte is auto-reactive against such antigens, it undergoes either negative selection, via apoptosis, or differentiation into the regulatory T cell lineage. This induction of central tolerance is critical for prevention of autoimmunity. Chemokines and adhesion molecules play an essential role in tolerance induction, as they promote migration of developing thymocytes through the different thymic microenvironments and enhance interactions with APCs displaying self-antigens. Herein, we review the contribution of chemokines and other regulators of thymocyte localization and motility to T cell development, with a focus on their contribution to the induction of central tolerance.

No MeSH data available.


Related in: MedlinePlus

Thymocyte migration through distinct thymic microenvironments occurs in an ordered fashion, enabling appropriate interactions with stromal cells. Thymocyte progenitors enter the thymus through vessels at the cortico-medullary junction (CMJ). ETPs (CD3−CD4−CD8−c-Kit+CD44+CD25−) integrate cTEC-derived signals in the cortex near the CMJ, which promote survival and T-lineage-commitment. DN2 (CD3−CD4−CD8−c-Kit+CD44+CD25+) thymocytes migrate into the mid-cortex, as they rearrange TCRβ chain genes. Subsequent DN3 (CD3−CD4−CD8−c-Kit−CD44−CD25+) thymocytes that pass the β-selection checkpoint proliferate at the sub-capsule, and differentiate through a DN4 (CD3−CD4−CD8−c-Kit−CD44−CD25−) stage to become DP (CD4+CD8+) thymocytes. DP cells, which rearrange TCRα chain genes, are localized throughout the cortex, with a bias toward the medulla. Interactions with cTECs induce positive selection of DP cells expressing TCRs with low avidity for self-peptide:MHCs. Auto-reactive DP thymocytes can be negatively selected in the cortex. Positively selected DP cells begin to migrate rapidly and enter the thymic medulla, guided by chemokine gradients, as they differentiate into SP thymocytes. SP cells rapidly scan mTECs and DCs during their 4–5-day residence time in the medulla to encounter a wide array of self-peptides, which induce auto-reactive cells to undergo apoptosis or diversion into the Treg lineage. Mature SP thymocytes egress from the thymus through blood vessels in the CMJ.
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Figure 1: Thymocyte migration through distinct thymic microenvironments occurs in an ordered fashion, enabling appropriate interactions with stromal cells. Thymocyte progenitors enter the thymus through vessels at the cortico-medullary junction (CMJ). ETPs (CD3−CD4−CD8−c-Kit+CD44+CD25−) integrate cTEC-derived signals in the cortex near the CMJ, which promote survival and T-lineage-commitment. DN2 (CD3−CD4−CD8−c-Kit+CD44+CD25+) thymocytes migrate into the mid-cortex, as they rearrange TCRβ chain genes. Subsequent DN3 (CD3−CD4−CD8−c-Kit−CD44−CD25+) thymocytes that pass the β-selection checkpoint proliferate at the sub-capsule, and differentiate through a DN4 (CD3−CD4−CD8−c-Kit−CD44−CD25−) stage to become DP (CD4+CD8+) thymocytes. DP cells, which rearrange TCRα chain genes, are localized throughout the cortex, with a bias toward the medulla. Interactions with cTECs induce positive selection of DP cells expressing TCRs with low avidity for self-peptide:MHCs. Auto-reactive DP thymocytes can be negatively selected in the cortex. Positively selected DP cells begin to migrate rapidly and enter the thymic medulla, guided by chemokine gradients, as they differentiate into SP thymocytes. SP cells rapidly scan mTECs and DCs during their 4–5-day residence time in the medulla to encounter a wide array of self-peptides, which induce auto-reactive cells to undergo apoptosis or diversion into the Treg lineage. Mature SP thymocytes egress from the thymus through blood vessels in the CMJ.

Mentions: Thymocytes migrate through distinct thymic microenvironments at discrete stages of differentiation in order to receive essential signals from surrounding stromal cells that govern further differentiation and selection (1, 2) (Figure 1). Early thymocyte progenitors (ETP) localize to the cortical side of the cortico-medullary junction (CMJ). As they commit to the T-lineage, thymocytes migrate into the mid-cortex, where they rearrange T cell receptor (TCR) β chain genes (3). Cells that successfully express TCRβ pass the β-selection checkpoint, and undergo proliferation and differentiation near the sub-capsule. Subsequent double positive (DP) thymocytes are localized throughout the cortex, where they rearrange TCRα chain genes. DP cells that receive weak TCR signals in the cortex undergo positive selection, promoting survival and differentiation of self-MHC-restricted single positive (SP) cells. SP thymocytes migrate into the medulla, where auto-reactive cells receiving strong TCR signals are culled from the repertoire or diverted into the regulatory T cell (Treg) lineage. We will review migratory and adhesion cues governing localization and cellular interactions of differentiating thymocytes and stromal cell subsets, with an emphasis on signals that promote central tolerance. Recent advances and open questions will be highlighted.


The Contribution of Chemokines and Migration to the Induction of Central Tolerance in the Thymus.

Hu Z, Lancaster JN, Ehrlich LI - Front Immunol (2015)

Thymocyte migration through distinct thymic microenvironments occurs in an ordered fashion, enabling appropriate interactions with stromal cells. Thymocyte progenitors enter the thymus through vessels at the cortico-medullary junction (CMJ). ETPs (CD3−CD4−CD8−c-Kit+CD44+CD25−) integrate cTEC-derived signals in the cortex near the CMJ, which promote survival and T-lineage-commitment. DN2 (CD3−CD4−CD8−c-Kit+CD44+CD25+) thymocytes migrate into the mid-cortex, as they rearrange TCRβ chain genes. Subsequent DN3 (CD3−CD4−CD8−c-Kit−CD44−CD25+) thymocytes that pass the β-selection checkpoint proliferate at the sub-capsule, and differentiate through a DN4 (CD3−CD4−CD8−c-Kit−CD44−CD25−) stage to become DP (CD4+CD8+) thymocytes. DP cells, which rearrange TCRα chain genes, are localized throughout the cortex, with a bias toward the medulla. Interactions with cTECs induce positive selection of DP cells expressing TCRs with low avidity for self-peptide:MHCs. Auto-reactive DP thymocytes can be negatively selected in the cortex. Positively selected DP cells begin to migrate rapidly and enter the thymic medulla, guided by chemokine gradients, as they differentiate into SP thymocytes. SP cells rapidly scan mTECs and DCs during their 4–5-day residence time in the medulla to encounter a wide array of self-peptides, which induce auto-reactive cells to undergo apoptosis or diversion into the Treg lineage. Mature SP thymocytes egress from the thymus through blood vessels in the CMJ.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4528182&req=5

Figure 1: Thymocyte migration through distinct thymic microenvironments occurs in an ordered fashion, enabling appropriate interactions with stromal cells. Thymocyte progenitors enter the thymus through vessels at the cortico-medullary junction (CMJ). ETPs (CD3−CD4−CD8−c-Kit+CD44+CD25−) integrate cTEC-derived signals in the cortex near the CMJ, which promote survival and T-lineage-commitment. DN2 (CD3−CD4−CD8−c-Kit+CD44+CD25+) thymocytes migrate into the mid-cortex, as they rearrange TCRβ chain genes. Subsequent DN3 (CD3−CD4−CD8−c-Kit−CD44−CD25+) thymocytes that pass the β-selection checkpoint proliferate at the sub-capsule, and differentiate through a DN4 (CD3−CD4−CD8−c-Kit−CD44−CD25−) stage to become DP (CD4+CD8+) thymocytes. DP cells, which rearrange TCRα chain genes, are localized throughout the cortex, with a bias toward the medulla. Interactions with cTECs induce positive selection of DP cells expressing TCRs with low avidity for self-peptide:MHCs. Auto-reactive DP thymocytes can be negatively selected in the cortex. Positively selected DP cells begin to migrate rapidly and enter the thymic medulla, guided by chemokine gradients, as they differentiate into SP thymocytes. SP cells rapidly scan mTECs and DCs during their 4–5-day residence time in the medulla to encounter a wide array of self-peptides, which induce auto-reactive cells to undergo apoptosis or diversion into the Treg lineage. Mature SP thymocytes egress from the thymus through blood vessels in the CMJ.
Mentions: Thymocytes migrate through distinct thymic microenvironments at discrete stages of differentiation in order to receive essential signals from surrounding stromal cells that govern further differentiation and selection (1, 2) (Figure 1). Early thymocyte progenitors (ETP) localize to the cortical side of the cortico-medullary junction (CMJ). As they commit to the T-lineage, thymocytes migrate into the mid-cortex, where they rearrange T cell receptor (TCR) β chain genes (3). Cells that successfully express TCRβ pass the β-selection checkpoint, and undergo proliferation and differentiation near the sub-capsule. Subsequent double positive (DP) thymocytes are localized throughout the cortex, where they rearrange TCRα chain genes. DP cells that receive weak TCR signals in the cortex undergo positive selection, promoting survival and differentiation of self-MHC-restricted single positive (SP) cells. SP thymocytes migrate into the medulla, where auto-reactive cells receiving strong TCR signals are culled from the repertoire or diverted into the regulatory T cell (Treg) lineage. We will review migratory and adhesion cues governing localization and cellular interactions of differentiating thymocytes and stromal cell subsets, with an emphasis on signals that promote central tolerance. Recent advances and open questions will be highlighted.

Bottom Line: As T cells develop, they migrate throughout the thymus where they undergo essential bi-directional signaling with stromal cells in distinct thymic microenvironments.Antigen-presenting cells (APCs) within the cortex and medulla display peptides derived from a wide array of self-proteins, which promote thymocyte self-tolerance.Chemokines and adhesion molecules play an essential role in tolerance induction, as they promote migration of developing thymocytes through the different thymic microenvironments and enhance interactions with APCs displaying self-antigens.

View Article: PubMed Central - PubMed

Affiliation: Ehrlich Laboratory, Department of Molecular Biosciences, Institute for Cellular and Molecular Biology, The University of Texas at Austin , Austin, TX , USA.

ABSTRACT
As T cells develop, they migrate throughout the thymus where they undergo essential bi-directional signaling with stromal cells in distinct thymic microenvironments. Immature thymocyte progenitors are located in the thymic cortex. Following T cell receptor expression and positive selection, thymocytes undergo a dramatic transition: they become rapidly motile and relocate to the thymic medulla. Antigen-presenting cells (APCs) within the cortex and medulla display peptides derived from a wide array of self-proteins, which promote thymocyte self-tolerance. If a thymocyte is auto-reactive against such antigens, it undergoes either negative selection, via apoptosis, or differentiation into the regulatory T cell lineage. This induction of central tolerance is critical for prevention of autoimmunity. Chemokines and adhesion molecules play an essential role in tolerance induction, as they promote migration of developing thymocytes through the different thymic microenvironments and enhance interactions with APCs displaying self-antigens. Herein, we review the contribution of chemokines and other regulators of thymocyte localization and motility to T cell development, with a focus on their contribution to the induction of central tolerance.

No MeSH data available.


Related in: MedlinePlus