An Essential Role for Medullary Thymic Epithelial Cells during the Intrathymic Development of Invariant NKT Cells

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An Essential Role for Medullary Thymic Epithelial Cells during the Intrathymic Development of Invariant NKT Cells. / White, Andrea J; Jenkinson, William; Cowan, Jennifer E; Parnell, Sonia M; Bacon, Andrea; Jones, Nick D; Jenkinson, Eric J; Anderson, Graham.

In: Journal of Immunology, Vol. 192, No. 6, 15.03.2014, p. 2659-66.

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@article{fac4d24f8b5640829c4aaeb511ab3940,
title = "An Essential Role for Medullary Thymic Epithelial Cells during the Intrathymic Development of Invariant NKT Cells",
abstract = "In the thymus, interactions with both cortical and medullary microenvironments regulate the development of self-tolerant conventional CD4(+) and CD8(+) αβT cells expressing a wide range of αβTCR specificities. Additionally, the cortex is also required for the development of invariant NKT (iNKT) cells, a specialized subset of T cells that expresses a restricted αβTCR repertoire and is linked to the regulation of innate and adaptive immune responses. Although the role of the cortex in this process is to enable recognition of CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors, the requirements for additional thymus microenvironments during iNKT cell development are unknown. In this study, we reveal a role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus. This requirement for mTECs correlates with their expression of genes required for IL-15 trans-presentation, and we show that soluble IL-15/IL-15Rα complexes restore iNKT cell development in the absence of mTECs. Furthermore, mTEC development is abnormal in iNKT cell-deficient mice, and early stages in iNKT cell development trigger receptor activator for NF-κB ligand-mediated mTEC development. Collectively, our findings demonstrate that intrathymic iNKT cell development requires stepwise interactions with both the cortex and the medulla, emphasizing the importance of thymus compartmentalization in the generation of both diverse and invariant αβT cells. Moreover, the identification of a novel requirement for iNKT cells in thymus medulla development further highlights the role of both innate and adaptive immune cells in thymus medulla formation.",
author = "White, {Andrea J} and William Jenkinson and Cowan, {Jennifer E} and Parnell, {Sonia M} and Andrea Bacon and Jones, {Nick D} and Jenkinson, {Eric J} and Graham Anderson",
year = "2014",
month = mar,
day = "15",
doi = "10.4049/jimmunol.1303057",
language = "English",
volume = "192",
pages = "2659--66",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "6",

}

RIS

TY - JOUR

T1 - An Essential Role for Medullary Thymic Epithelial Cells during the Intrathymic Development of Invariant NKT Cells

AU - White, Andrea J

AU - Jenkinson, William

AU - Cowan, Jennifer E

AU - Parnell, Sonia M

AU - Bacon, Andrea

AU - Jones, Nick D

AU - Jenkinson, Eric J

AU - Anderson, Graham

PY - 2014/3/15

Y1 - 2014/3/15

N2 - In the thymus, interactions with both cortical and medullary microenvironments regulate the development of self-tolerant conventional CD4(+) and CD8(+) αβT cells expressing a wide range of αβTCR specificities. Additionally, the cortex is also required for the development of invariant NKT (iNKT) cells, a specialized subset of T cells that expresses a restricted αβTCR repertoire and is linked to the regulation of innate and adaptive immune responses. Although the role of the cortex in this process is to enable recognition of CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors, the requirements for additional thymus microenvironments during iNKT cell development are unknown. In this study, we reveal a role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus. This requirement for mTECs correlates with their expression of genes required for IL-15 trans-presentation, and we show that soluble IL-15/IL-15Rα complexes restore iNKT cell development in the absence of mTECs. Furthermore, mTEC development is abnormal in iNKT cell-deficient mice, and early stages in iNKT cell development trigger receptor activator for NF-κB ligand-mediated mTEC development. Collectively, our findings demonstrate that intrathymic iNKT cell development requires stepwise interactions with both the cortex and the medulla, emphasizing the importance of thymus compartmentalization in the generation of both diverse and invariant αβT cells. Moreover, the identification of a novel requirement for iNKT cells in thymus medulla development further highlights the role of both innate and adaptive immune cells in thymus medulla formation.

AB - In the thymus, interactions with both cortical and medullary microenvironments regulate the development of self-tolerant conventional CD4(+) and CD8(+) αβT cells expressing a wide range of αβTCR specificities. Additionally, the cortex is also required for the development of invariant NKT (iNKT) cells, a specialized subset of T cells that expresses a restricted αβTCR repertoire and is linked to the regulation of innate and adaptive immune responses. Although the role of the cortex in this process is to enable recognition of CD1d molecules expressed by CD4(+)CD8(+) thymocyte precursors, the requirements for additional thymus microenvironments during iNKT cell development are unknown. In this study, we reveal a role for medullary thymic epithelial cells (mTECs) during iNKT cell development in the mouse thymus. This requirement for mTECs correlates with their expression of genes required for IL-15 trans-presentation, and we show that soluble IL-15/IL-15Rα complexes restore iNKT cell development in the absence of mTECs. Furthermore, mTEC development is abnormal in iNKT cell-deficient mice, and early stages in iNKT cell development trigger receptor activator for NF-κB ligand-mediated mTEC development. Collectively, our findings demonstrate that intrathymic iNKT cell development requires stepwise interactions with both the cortex and the medulla, emphasizing the importance of thymus compartmentalization in the generation of both diverse and invariant αβT cells. Moreover, the identification of a novel requirement for iNKT cells in thymus medulla development further highlights the role of both innate and adaptive immune cells in thymus medulla formation.

U2 - 10.4049/jimmunol.1303057

DO - 10.4049/jimmunol.1303057

M3 - Article

C2 - 24510964

VL - 192

SP - 2659

EP - 2666

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 6

ER -