Sertoli Cell Immune Regulation: A Double-Edged Sword

Abstract

The testis must create and maintain an immune privileged environment to protect maturing germ cells from autoimmune destruction. The establishment of this protective environment is due, at least in part, to Sertoli cells. Sertoli cells line the seminiferous tubules and form the blood-testis barrier (BTB), a barrier between advanced germ cells and the immune system. The BTB compartmentalizes the germ cells and facilitates the appropriate microenvironment necessary for spermatogenesis. Further, Sertoli cells modulate innate and adaptive immune processes through production of immunoregulatory compounds. Sertoli cells, when transplanted ectopically (outside the testis), can also protect transplanted tissue from the recipient's immune system and reduce immune complications in autoimmune diseases primarily by immune regulation. These properties make Sertoli cells an attractive candidate for inflammatory disease treatments and cell-based therapies. Conversely, the same properties that protect the germ cells also allow the testis to act as a reservoir site for infections. Interestingly, Sertoli cells also have the ability to mount an antimicrobial response, if necessary, as in the case of infections. This review aims to explore how Sertoli cells act as a double-edged sword to both protect germ cells from an autoimmune response and activate innate and adaptive immune responses to fight off infections.

Keywords: Sertoli cells; cell therapeutics; immune regulation; testis; transplantation.

Figure 1

Structure of the seminiferous tubule. Spermatogenesis takes place within the seminiferous tubules. These tubules are surrounded by peritubular myoid cells and contain the germ cells engulfed by Sertoli cells. The BTB between adjacent Sertoli cells separates the seminiferous epithelium into the basal and adluminal compartments. Blood vessels, Leydig cells, and testicular macrophages are located outside the tubules in the testis interstitium.

Figure 2

The Sertoli cell double-edged sword. Sertoli cells express many different immunomodulatory factors that allow them to protect germ cells from both infection and immune responses.

Figure 3

The complement system. Activation of complement leads to the formation of two convertases, which then lead to opsonization of target cells, secretion of proinflammatory anaphylatoxins and insertion of the MAC pore. These functions of complement work together to destroy pathogens but can also destroy host cells if not properly regulated. Red text indicates known complement inhibitors expressed by Sertoli cells.

Figure 4

Immune regulation in the testis. Under normal circumstances, cells in the testis (including Sertoli cells) produce immunoregulatory factors that favor the presence of regulatory immune cells, including M2 macrophages, Tregs, and tolerogenic dendritic cells, that maintain a milieu supporting germ cell survival. On the other hand, if bacteria and viruses invade the testis, to eliminate the pathogen, the testis can initiate an inflammatory response that includes activation of PRRs, production of inflammatory cytokines and antimicrobial factors, and recruitment and activation of inflammatory immune cells such as M1 macrophages and cytotoxic T cells. If this response to infection is kept in check it does not disrupt normal testicular function and the testis is able to maintains a delicate balance to promote spermatogenesis and prevent infection. However, if it gets out of control, inflammation in the testis can lead to disruption of the BTB and loss of germ cells. At the same time, if the response is not strong enough to eliminate the infection, it can lead to a sanctuary reservoir for viruses and bacteria. Solid red lines indicate inhibition and dashed green lines indicate potential (but not proven) functions.