Naslov
Upregulation of thymic expression of gp96, TGF-beta and induction of regulatory T cells by partial hepatectomy

Autori
Jakovac, Hrvoje ; Radošević-Stašić, Biserka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstract book / Bojan Polić, Croatian Immunological Society - Rijeka : EFIS, Medicinski fakultet, Sveučilište u Rijeci, 2013, 85-85

Skup
2nd Meeting of Middle-European Societies for Immunology and Allergology

Mjesto i datum
Opatija, Hrvatska, 10.10.2013. - 13.10.2013

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
partial hepatectomy; thymus; central tolerance

Sažetak
Background: Liver regeneration that follows partial hepatectomy (pHx) is a well-known model for investigating mechanisms related with the control of normal growth and maintenance of morphostasis. The process is characterized by 1) initial priming phase, linked with cytokine induction, 2) proliferative phase, related with growth-factor-induced progression of cells through the G1 restriction point and 3) growth termination phase, induced by inhibitory factors TGF and IL1. Activating and inhibiting signals come from the parenchymal and nonparenchymal cells in the liver, but also from the peripheral organs and the thymus, showing that regeneration of the liver is regulated by cooperative signals from various sources. Moreover, in the control of reparatory processes participate the autoreactive lymphocyte clones with regulatory and protective effects, such as CD1-restricted NKT cells that express a semi-invariant T-cell receptor specific for conserved self ligands and CD4+CD25+Foxp3+ regulatory T cells (TReg) cells, which may have a strong influence on reestablishment of self-tolerance after disturbance of morphostasis. Material and methods: In an attempt to enlarge our previous findings, pointing to the involvement of endoplasmic reticulum (ER)-resident heat shock proteins (HSP) in these events, in the thymus of mice subjected to pHx we estimated the expression of gp96, CD91, TLR2 and TGF-, and the distribution of TReg cells and cells reactive to Dolichos biflorus agglutinin (DBA) lectin. The data, obtained by immunohistochemistry and real-time PCR (for the detection of gp96 mRNA) were compared with findings in intact and sham operated mice. Results: The data have shown that 1/3 pHx in C57/BL6 mice leads to high upregulation of gp96 in the thymic cortex (on stromal and epithelial cells and some lymphatic cells), and to the enhanced expression of its receptors - CD91 and TLR2 that are responsible for endocytosis of gp96-chaperoned peptides and for the intracellular activation of ER-stress pathways, respectively. The highest increase in the expression of gp96 protein was observed 48h after pHx, i.e. at the time when the high apoptosis of thymocytes was also seen. At the transcriptional level, two peaks of gp96 mRNA were detected (at 2h and at 48h after pHx). Additionally, it has been found that pHx induces a marked upregulation of TGF- immunoreactivity in cortical areas. Simultaneously, in thymic cortex increased the number of DBA+ cells that are specific for terminal alpha-linked N-acetyl-D-galactosamine residues. Several of these cells were in direct contact with cells expressing gp96 or exhibited the cytoplasmic gp96 immunopositivity. Furthermore, 48h after pHx, in the cortex of thymus, numerous CD4+/Foxp3+ and CD25+/Foxp3+ T cells were found, indicating that pHx has stimulated also the generation of regulatory T cells. Conclusion: The data imply that liver regeneration is followed by breakdown of central tolerance to self-antigens and show that ER-resident HSP-gp96 may participate in ER-quality control and in the interactions that determine the positive and negative selection events during normal thymocyte differentiation. Mechanisms are unclear, but there is a high possibility that gp96 participated in the maintenance of immunologic self-tolerance, acting as a chaperon of self-peptides and/or as a factor responsible for the delivery of co-stimulatory signals by classical and non-classical APC in thymic epithelial network. The data point also to the importance of glycosylation in various steps of T-cell development and suggest that upregulated TGF- in the thymic cortex may contribute to the positive selection of TReg cells, which during liver regeneration might be involved in the restrain the fast liver growth and in the suppression of transient autoimmune events activated by pHx.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti

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