Characterization of Human Thymic Exosomes

Skogberg, Gabriel; Gudmundsdottir, Judith; Post, Sjoerd van der; Sandström, Kerstin; Bruhn, Sören; Benson, Mikael; Mincheva‐Nilsson, Lucia; Baranov, Vladimir; Telemo, Esbjörn; Ekwall, Olov

doi:10.1371/journal.pone.0067554

Cited by 63 publications

(79 citation statements)

References 50 publications

(55 reference statements)

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“…We have previously reported that human thymic exosomes display a protein content including TRAs, miRNA and surface markers which together indicate a thymic epithelial cell origin16. In the current study, we identify exosomes as key regulators of late stage thymocyte maturation in vitro .…”

Section: Discussionmentioning

confidence: 59%

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Thymic exosomes promote the final maturation of thymocytes

Lundberg

Berglund

Skogberg

et al. 2016

Sci Rep

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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.

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Section: Discussionmentioning

confidence: 59%

“…Furthermore, intestinal epithelial derived exosomes have been shown to mediate MHC class II-dependent immune tolerance to dietary antigens14. The presence of exosomes is established both in the murine and human thymus, but their function is less well studied1516.…”

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confidence: 99%

Thymic exosomes promote the final maturation of thymocytes

Lundberg

Berglund

Skogberg

et al. 2016

Sci Rep

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“…Because it has been speculated that exosomes may participate in the shuttling of TRAs from stromal cells to thymocytes or DCs (39, 40) and we and others have shown that thymic tissue is rich in exosomes (18,19), we have taken interest in the characteristics and functions of thymic exosomes. When we investigated the protein profiles of thymic exosomes from DS and control patients, the proteins in exosomes from DS patients represent a greater diversity than the proteins from control exosomes (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Previous investigations of DS thymic tissue have described a decrease in thymic size (13), altered thymocyte subpopulations (14), increased thymocyte depletion, markedly enlarged Hassall's corpuscles (HCs) (15), decreased thymic output (16), and a decrease in the number of AIRE + cells in the medullary region (17). The thymic tissue also produce exosomes (18,19), which are small membrane-bound vesicles that are released by various types of cells. Exosomes are important for intercellular communication and carry proteins, nucleic acids, and lipids (20).…”

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Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

Skogberg

Lundberg

Lindgrén

et al. 2014

The Journal of Immunology

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Down syndrome (DS), caused by trisomy of chromosome 21, is associated with immunological dysfunctions such as increased frequency of infections and autoimmune diseases. Patients with DS share clinical features, such as autoimmune manifestations and specific autoantibodies, with patients affected by autoimmune polyendocrine syndrome type 1. Autoimmune polyendocrine syndrome type 1 is caused by mutations in the autoimmune regulator (AIRE) gene, located on chromosome 21, which regulates the expression of tissue-restricted Ags (TRAs) in thymic epithelial cells. We investigated the expression of AIRE and TRAs in DS and control thymic tissue using quantitative PCR. AIRE mRNA levels were elevated in thymic tissue from DS patients, and trends toward increased expression of the AIRE-controlled genes INSULIN and CHRNA1 were found. Immunohistochemical stainings showed altered cell composition and architecture of the thymic medulla in DS individuals with increased frequencies of AIRE-positive medullary epithelial cells and CD11c-positive dendritic cells as well as enlarged Hassall’s corpuscles. In addition, we evaluated the proteomic profile of thymic exosomes in DS individuals and controls. DS exosomes carried a broader protein pool and also a larger pool of unique TRAs compared with control exosomes. In conclusion, the increased AIRE gene dose in DS could contribute to an autoimmune phenotype through multiple AIRE-mediated effects on homeostasis and function of thymic epithelial cells that affect thymic selection processes.

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c‐Src, Insulin‐Like Growth Factor I Receptor, G‐Protein‐Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes

DeRita

Zerlanko

Singh

et al. 2016

J of Cellular Biochemistry

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It is well known that Src tyrosine kinase, insulin-like growth factor 1 receptor (IGF-IR), and focal adhesion kinase (FAK) play important roles in prostate cancer (PrCa) development and progression. Src, which signals through FAK in response to integrin activation, has been implicated in many aspects of tumor biology, such as cell proliferation, metastasis and angiogenesis. Furthermore, Src signaling is known to crosstalk with IGF-IR, which also promotes tumor growth and angiogenesis. In this study, we demonstrate that c-Src, IGF-IR and FAK are packaged into exosomes (Exo), c-Src in particular being highly enriched in Exo from the androgen receptor (AR)-positive cell line C4-2B and AR-negative cell lines PC3 and DU145. Furthermore, we show that the active phosphorylated form of Src (SrcpY416) is co-expressed in Exo with phosphorylated FAK (FAKpY861), a known target site of Src, which enhances proliferation and migration. We further demonstrate for the first time exosomal enrichment of G-protein-coupled receptor kinase (GRK) 5 and GRK6, both of which regulate Src and IGF-IR signaling and have been implicated in cancer. Finally, SrcpY416 and c-Src are both expressed in Exo isolated from the plasma of prostate tumor-bearing TRAMP mice, and those same mice have higher levels of exosomal c-Src than their wild-type counterparts. In summary, we provide new evidence that active signaling molecules relevant to PrCa are enriched in Exo, and this suggests that the Src signaling network may provide useful biomarkers detectable by liquid biopsy, and may contribute to PrCa progression via Exo.

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Characterization of Human Thymic Exosomes

Cited by 63 publications

References 50 publications

Thymic exosomes promote the final maturation of thymocytes

Thymic exosomes promote the final maturation of thymocytes

Altered Expression of Autoimmune Regulator in Infant Down Syndrome Thymus, a Possible Contributor to an Autoimmune Phenotype

c‐Src, Insulin‐Like Growth Factor I Receptor, G‐Protein‐Coupled Receptor Kinases and Focal Adhesion Kinase are Enriched Into Prostate Cancer Cell Exosomes

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