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

Andrea J White,Eric J Jenkinson,Graham Anderson,Jennifer E Cowan,Nick D Jones,Sonia M Parnell,William E Jenkinson,Andrea Bacon

doi:10.4049/jimmunol.1303057

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.

Highlights

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Analysis of WT and Relb2/2 thymic epithelial cell (TEC) grafts recovered after 8 wk showed that despite comparable numbers of total and CD4+CD8+ thymocytes, Relb2/2 TEC grafts contained a significant reduction in both the proportion and absolute cell number of PBS57/CD1d tetramer+ invariant NKT (iNKT) cells (Fig. 1A, 1B)
We show that normal development of both RORgt2 and RORgt+ “iNKT17” [20] cells depends on the presence of medullary thymic epithelial cell (mTEC), indicating common microenvironmental requirements for the development of discrete iNKT cell populations

Summary

Introduction

Whereas induction of iNKT cell development occurs independently of mTECs, a finding in line with their initial selection by cortical thymocytes present in normal frequencies in Relb2/2 TEC grafts (Fig. 1B), later stages of We transplanted either CD80/ CD86 double-knockout (B7-1/B7-22/2) or ICOSL knockout (B7h2/2) TECs under the kidney capsule of WT mice, generating thymic microenvironments in which either CD80/86 or ICOSL expression was selectively absent from mTECs. Analysis of development in WT, B7h2/2, and B7-1/B7-22/2 TEC grafts showed no differences in the proportions (Fig. 2B) and absolute numbers of iNKT cell subsets (Fig. 2C), indicating that the requirement for mTECs does not map to expression of B7 molecules.

Results

Conclusion