Thymic exosomes promote the final maturation of thymocytes.

Vanja Lundberg,Susanne Lindgren,Judith Gudmundsdottir,Gabriel Skogberg,Esbjörn Telemo,Christina Lundqvist,Olov Ekwall,Martin Berglund,Karolina Thörn

doi:10.1038/srep36479

Vanja Lundberg, Susanne Lindgren + Show 7 more

Open Access

https://doi.org/10.1038/srep36479

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Journal: Scientific Reports	Publication Date: Nov 8, 2016
Citations: 23	License type: CC BY 4.0

Affiliation: University of Gothenburg

Abstract

Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. Less is known regarding other important processes in the thymic medulla such as the regulation of late stage thymocyte maturation. We have previously reported that exosomes are abundant in the thymus with a phenotype that indicates an epithelial cell origin and immunoregulatory properties. In this study we use an in vitro system to investigate the effects of thymic exosomes on the maturation of single positive thymocytes as well as effects on nTreg formation. We show that thymic exosomes promote the maturation of single positive CD4+CD25− cells into mature thymocytes with S1P1+Qa2+ and CCR7+Qa2+ phenotypes. Furthermore, we show that thymic exosomes reduce the formation of CD4+CD25+FoxP3+ thymocytes and that these exosome effects are independent of dendritic cell co-stimulation but require intact exosomal RNA content and surface proteins. An efficient direct uptake of exosomes by both thymocytes and thymic DC’s is also demonstrated. In conclusion, this study demonstrates that exosomes may represent a new route of communication within the thymus.

Highlights

Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla
A key stromal cell population is the medullary thymic epithelial cells, which express many otherwise tissue-restricted antigens (TRAs) that are crucial for the negative selection process[3,4], and for the formation of the nTreg population
We demonstrate that thymic exosomes stimulate maturation of CD4+CD25− single positive (SP) thymocytes into an S1P1+Qa2+ and S1P1+CCR7+ phenotype and reduce the formation of CD25+FoxP3+ thymocytes

Summary

Introduction

Extensive knowledge has been gained the last years concerning mechanisms underlying the selection of single positive thymocytes in the thymic medulla. A key stromal cell population is the medullary thymic epithelial cells (mTECs), which express many otherwise tissue-restricted antigens (TRAs) that are crucial for the negative selection process[3,4], and for the formation of the nTreg population. Aire has been implicated to be important for antigen transfer from mTECs to dendritic cells (DCs) as well as for regulation of the expression of mTEC specific miRNAs important for TRA expression and TEC maturation[7,8]. The thymocytes change their gene expression profile and up-regulate genes involved in late stage maturation, thymic egress and extrathymic functions. One such gene is the Kruppel-like factor 2 (KLF2), which drives the gene expression of both S1P1 and CD62L in SP thymocytes[20]. Qa2 is a non-classical MHC class I molecule used as a marker for thymocyte maturation and expression of Qa2 is up-regulated in the final SP4 stage of thymocyte development just before their exit to the periphery[26,27]

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