Differentiation of regulatory Foxp3+ T cells in the thymic cortex

Adrian Liston, Katherine M. Nutsch, Andrew G. Farr, Jennifer M. Lund, Jeffery P. Rasmussen, Pandelakis Koni, Alexander Y. Rudensky

Research output: Contribution to journalArticle

137 Citations (Scopus)

Abstract

Regulatory Foxp3+ T cells (TR) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)-ligand interactions within a certain increased affinity range, in conjunction with γc-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the TR lineage. The contribution of distinct MHC class II-expressing accessory cell types to the differentiation process of Foxp3 + thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting TR differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3+ thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3+ thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3+ T cells.

Original languageEnglish (US)
Pages (from-to)11903-11908
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number33
DOIs
StatePublished - Aug 19 2008

Fingerprint

Regulatory T-Lymphocytes
Thymocytes
Epithelial Cells
Dendritic Cells
Cytokine Receptors
T-Cell Antigen Receptor
Cell Differentiation
Up-Regulation
Pathology
Ligands

Keywords

  • Immune tolerance
  • Selection
  • Thymus

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Liston, A., Nutsch, K. M., Farr, A. G., Lund, J. M., Rasmussen, J. P., Koni, P., & Rudensky, A. Y. (2008). Differentiation of regulatory Foxp3+ T cells in the thymic cortex. Proceedings of the National Academy of Sciences of the United States of America, 105(33), 11903-11908. https://doi.org/10.1073/pnas.0801506105

Differentiation of regulatory Foxp3+ T cells in the thymic cortex. / Liston, Adrian; Nutsch, Katherine M.; Farr, Andrew G.; Lund, Jennifer M.; Rasmussen, Jeffery P.; Koni, Pandelakis; Rudensky, Alexander Y.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 33, 19.08.2008, p. 11903-11908.

Research output: Contribution to journalArticle

Liston, A, Nutsch, KM, Farr, AG, Lund, JM, Rasmussen, JP, Koni, P & Rudensky, AY 2008, 'Differentiation of regulatory Foxp3+ T cells in the thymic cortex', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 33, pp. 11903-11908. https://doi.org/10.1073/pnas.0801506105
Liston, Adrian ; Nutsch, Katherine M. ; Farr, Andrew G. ; Lund, Jennifer M. ; Rasmussen, Jeffery P. ; Koni, Pandelakis ; Rudensky, Alexander Y. / Differentiation of regulatory Foxp3+ T cells in the thymic cortex. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 33. pp. 11903-11908.
@article{ffeafbcd4fc14ea6b770c89c2b9a52d8,
title = "Differentiation of regulatory Foxp3+ T cells in the thymic cortex",
abstract = "Regulatory Foxp3+ T cells (TR) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)-ligand interactions within a certain increased affinity range, in conjunction with γc-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the TR lineage. The contribution of distinct MHC class II-expressing accessory cell types to the differentiation process of Foxp3 + thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting TR differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3+ thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3+ thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3+ T cells.",
keywords = "Immune tolerance, Selection, Thymus",
author = "Adrian Liston and Nutsch, {Katherine M.} and Farr, {Andrew G.} and Lund, {Jennifer M.} and Rasmussen, {Jeffery P.} and Pandelakis Koni and Rudensky, {Alexander Y.}",
year = "2008",
month = "8",
day = "19",
doi = "10.1073/pnas.0801506105",
language = "English (US)",
volume = "105",
pages = "11903--11908",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "33",

}

TY - JOUR

T1 - Differentiation of regulatory Foxp3+ T cells in the thymic cortex

AU - Liston, Adrian

AU - Nutsch, Katherine M.

AU - Farr, Andrew G.

AU - Lund, Jennifer M.

AU - Rasmussen, Jeffery P.

AU - Koni, Pandelakis

AU - Rudensky, Alexander Y.

PY - 2008/8/19

Y1 - 2008/8/19

N2 - Regulatory Foxp3+ T cells (TR) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)-ligand interactions within a certain increased affinity range, in conjunction with γc-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the TR lineage. The contribution of distinct MHC class II-expressing accessory cell types to the differentiation process of Foxp3 + thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting TR differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3+ thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3+ thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3+ T cells.

AB - Regulatory Foxp3+ T cells (TR) are indispensable for preventing autoimmune pathology in multiple organs and tissues. During thymic differentiation T cell receptor (TCR)-ligand interactions within a certain increased affinity range, in conjunction with γc-containing cytokine receptor signals, induce Foxp3 expression and thereby commit developing thymocytes to the TR lineage. The contribution of distinct MHC class II-expressing accessory cell types to the differentiation process of Foxp3 + thymocytes remains controversial, because a unique role in this process has been ascribed to either thymic dendritic cells (tDC) or to medullary thymic epithelial cells (mTEC). Furthermore, it was suggested that the thymic medulla, where the bulk of the negative selection of self-reactive thymocytes takes place, provides a specialized microenvironment supporting TR differentiation. Here, we report that the cortex, as defined by cortical thymic epithelial cells (cTEC), is sufficient for supporting TR differentiation. MHC class II expression restricted to both cTEC and mTEC or to cTEC alone did not significantly affect the numbers of Foxp3+ thymocytes. Furthermore, genetic or pharmacologic blockade of thymocyte migration resulted in a prominent accumulation of Foxp3+ thymocytes in the cortex, demonstrating that secondary signals required for Foxp3 up-regulation exist in the cortex. Our results suggest that mTEC or tDC do not serve as a cell type singularly responsible for TR differentiation and that neither the cortex nor the medulla exclusively provides an environment suitable for Foxp3 induction. Instead, multiple accessory cell types probably contribute to the thymic generation of regulatory Foxp3+ T cells.

KW - Immune tolerance

KW - Selection

KW - Thymus

UR - http://www.scopus.com/inward/record.url?scp=50149099154&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50149099154&partnerID=8YFLogxK

U2 - 10.1073/pnas.0801506105

DO - 10.1073/pnas.0801506105

M3 - Article

VL - 105

SP - 11903

EP - 11908

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 33

ER -