Mouse Sertoli Cells Display Phenotypical and Functional Traits of Antigen-Presenting Cells in Response to Interferon Gamma

Abstract

The testis is regarded as an immunologically privileged site because it tolerates either autoantigenic germ cells or allografts. Because the blood testis barrier represents an incomplete immunological barrier, we have explored whether Sertoli cells, the somatic cells of the seminiferous epithelium, might play an active role in immune evasion. We report data indicating that B7-H1(officially known as CD274)-mediated co-inhibition, an immunomodulatory mechanism based on cell-cell interaction, can be activated in Sertoli cell-lymphocyte cocultures. We have found that, in response to interferon gamma (IFNG), mouse Sertoli cells strongly up-regulate the negative co-stimulatory ligand B7-H1 but remain devoid of positive co-stimulatory molecules. Blockade of B7-H1 on the Sertoli cell surface resulted in enhanced proliferation of CD8(+) T cells cocultured with Sertoli cells. Moreover, IFNG-stimulated Sertoli cells were found to express, concurrent with B7-H1, MHC class II. Therefore, we have hypothesized that Sertoli cells could function as nonprofessional tolerogenic antigen-presenting cells by inducing enrichment in regulatory T cells (Tregs) in a mixed T lymphocyte population. Interestingly, we found that coculturing T cells with Sertoli cells can indeed induce an increase in CD4(+)CD25(+)(officially known as IL2RA)FOXP3(+) Tregs and a decrease in CD4(+)CD25(-) T cells, suggesting Sertoli cell-mediated Treg conversion; this process was found to be B7-H1-independent. Altogether these data show that Sertoli cells are potentially capable of down-regulating the local immune response, on one hand by directly inhibiting CD8(+) T cell proliferation through B7-H1 and, on the other hand, by inducing an increase in Tregs that might suppress other bystander T cells.

Toll-Like Receptor 3 Activation Induces Antiviral Immune Responses in Mouse Sertoli Cells1

“…The first line of testicular defense against viruses arriving from the bloodstream is represented by the Leydig cells and testicular macrophages; the second line of defense involves the myoid cells lining the seminiferous tubules and Sertoli cells, responsible for maintenance of the blood-testis barrier that segregates the adluminal compartment containing autoantigenic germ cells [15,16]. Even under inflammatory stimuli, the Sertoli cell contributes to the maintenance of testicular immune privilege [17,18], following viral stimulation Leydig cells and Sertoli cells strongly respond in terms of IFN production. On the contrary, germ cells express very low levels of IFNs that are not significantly up-regulated by viral stimulation [19].…”

Differential Activation of Inflammatory Pathways in Testicular Macrophages Provides a Rationale for Their Subdued Inflammatory Capacity

“…Mechanisms implicated in the control of immune privilege include high levels of intratesticular androgens, and particularly immunosuppressive properties of local cells such as Sertoli cells in the seminiferous epithelium as well as regulatory T cells (Tregs) and macrophages in the interstitial space (1,5,6). One way how Sertoli cells induce testicular immune tolerance is by generation of Tregs (Foxp3 + Tregs) in a mechanism that triggers Notch/Jagged signaling pathways in these cells (7,8).…”

UropathogenicEscherichia coliBlock MyD88-Dependent and Activate MyD88-Independent Signaling Pathways in Rat Testicular Cells

“…The objective of this study was to determine how two types of bacteria (uropathogenic E. coli and nonpathogenic commensal E. coli) interact with testicular cells that are known to play an important role in pathogen recognition and defense signaling (5,23).…”