Thymic exosomes promote the final maturation of thymocytes

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.

Exosomes of pasteurized milk: potential pathogens of Western diseases

“…Notably, bovine milk exosomes contain both miR-155 and TGF-β [14,32,45], a fact, that further supports milk exosome-driven maturation of tTregs [18,19]. It is likely that milk exosomes or exosome-derived molecules, which reach distant tissue including the brain may also accumulate in the thymus [39], an organ exhibiting extensive exosome traffic [81][82][83]. Milk exosomes may thus support thymic epithelial cell-derived exosomes in tTreg differentiation and maturation, a potential augmenting mechanism which may explain allergy prevention early in life by consumption of raw cow's milk, during a period when the infant's thymus is still functional operative (Fig.…”

PPARgamma Deficiency Counteracts Thymic Senescence

“…Of note, as reported previously, overexpression of Wnt4 glycolipoproteins by thymic epithelial cells can efficiently counteract PPARgamma ( 31 ). Also, Wnt4 was described to travel in extracellular vesicles including exosomes and affect thymocyte differentiation ( 58 , 59 ). Hence, it is conceivable that thymic epithelium-derived, enriched exosomes would efficiently home to the thymus and deliver their Wnt4 cargo locally even when administered systemically.…”

Imaging Polarized Secretory Traffic at the Immune Synapse in Living T Lymphocytes

“…While exosomes are constitutively secreted by various cell lineages and tumor cells, in T and B lymphocytes exosome secretion is triggered upon activation of cell surface receptors, which in turn regulates antigen-specific immune responses ( 25 , 38 ). The exosomes participate in important processes related to TCR-triggered immune responses, including T lymphocyte-mediated cytotoxicity, AICD of CD4+ lymphocytes, antigen presentation, intercellular miRNA exchange ( 20 , 35 , 39 – 42 ), and thymus development ( 43 ). However, the mechanisms underlying MVB traffic and exosome secretion are poorly understood when compared with those corresponding to other secretory granules in T lymphocytes ( 21 , 44 , 45 ).…”