Immune-privileged Sertoli cells survive allotransplantation by inhibiting adaptive immune response
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Immune privileged Sertoli cells (SC) survive long-term and protect co-grafted cells when transplanted as allo- or xeno-grafts. However, their survival/protection mechanism remains unclear. The objective of this study was to investigate the immune privilege mechanism of SC. MSC-1 cells (a mouse Sertoli cell line), which lack some of the immunoprotective abilities associated with SC, as they are unable to survive in naïve immune competent animals, served as controls. SC and MSC-1 cells were transplanted as allografts into naïve BALB/c mice. SC survived throughout the study, whereas, very few MSC-1 cells were detected by day 11 and MSC-1 cell grafts were completely rejected within 20 days. To identify genes that are differentially regulated between SC and MSC-1 cells, microarray analysis was performed. 2369 genes with a ± 4-fold or higher level in SC compared to MSC-1 cells were obtained. Interestingly, genes involved in inhibiting adaptive immune response were upregulated in SC. Therefore, we hypothesized that SC survive as allografts by inhibiting humoral and/or cellular immune response. Analysis of SC or MSC-1 cell grafts and serum from transplanted animals for activation of humoral immune response revealed that antibody mediated cell death was not observed in either sets of grafts. Cell-mediated death (apoptosis) measured by TUNEL assay showed a significant increase in apoptotic cells at days 2, 5 and 8 in MSC-1 cell grafts, while very few apoptotic cells were observed in SC grafts. Immune cell infiltrate was examined and macrophages and CD4 T cells were detected in both sets of grafts. In contrast, SC grafts contained CD8 T cells, while little to no CD8 T cells were detected in MSC-1 cell grafts. Furthermore, early anti-inflammatory environment and T regulatory cells (CD4+Foxp3+ and CD8+Foxp3+ Tregs), associated with graft tolerance, were detected in SC grafts. MSC-1 cell grafts contained pro-inflammatory milieu and Tregs were either absent or very few were detected in rejected MSC-1 cell grafts. Overall, this led to the conclusion that SC have created a tolerogenic environment at the graft site by inhibiting humoral immune response, apoptosis and increasing the number of Tregs, which could be responsible for their long-term survival.