Sertoli cells--immunological sentinels of spermatogenesis

Abstract

Testicular germ cells, which appear after the establishment of central tolerance, express novel cell surface and intracellular proteins that can be recognized as 'foreign antigens' by the host's immune system. However, normally these germ cells do not evoke an auto-reactive immune response. The focus of this manuscript is to review the evidence that the blood-testis-barrier (BTB)/Sertoli cell (SC) barrier along with the SCs ability to modulate the immune response is vital for protecting auto-antigenic germ cells. In normal testis, the BTB/SC barrier protects the majority of the auto-antigenic germ cells by limiting access by the immune system and sequestering these 'new antigens'. SCs also modulate testis immune cells (induce regulatory immune cells) by expressing several immunoregulatory factors, thereby creating a local tolerogenic environment optimal for survival of nonsequesetred auto-antigenic germ cells. Collectively, the fortress created by the BTB/SC barrier along with modulation of the immune response is pivotal for completion of spermatogenesis and species survival.

Keywords: Blood–testis-barrier; Immune privilege; Sertoli cells; Spermatogenesis; Testis.

Figure 1

A) Localization of the BTB/SC barrier and cellular components of the testis. Testis interstitium consists of Leydig cells, macrophages (MΦ), tolerogenic DCs, T cells and blood vessels. The seminiferous tubules are composed of SCs and maturing germ cells surrounded by peritubular myoid cells. Tight junctions between adjacent SCs along with the body of the SCs form the BTB/SC barrier, which divides the tubules into the basal and adluminal compartments. B) Autoimmune orchitis. At the onset of orchitis, antibodies deposit on preleptotene spermatocytes present in the basal compartment of the tubules. Auto-reactive immune cells (cytotoxic MΦ and T cells) infiltrate the interstitium. C) Eventually, the disrupted BTB/SC barrier along with increased infiltration of auto-reactive immune cells results in arrest of spermatogenesis and germ cell loss. Y, auto-antibody.

Figure 2. Immune modulation by SCs

Immunoregulatory factors (such as TGF-β, IDO, galectin-1, activin A) expressed/secreted by SCs modulate the immune response to maintain a tolerogenic environment either directly, by inducing Tregs, or indirectly by inducing tolerogenic APCs (regulatory MΦ or tolerogenic DCs). These tolerogenic APCs present antigens to T cells either in the interstitium or testes draining lymph nodes and convert them into Tregs. Blue triangles, immunoregulatory factors.

Figure 3. Immune suppression by SCs

A) SCs inhibit proliferation of NK, B and T cells by expressing/secreting immunosuppressive factors. SCs also inhibit IL-2 production by T cells resulting in reduced proliferation. SCs express several apoptosis and complement inhibitors to prevent NK and T cell-mediated death, and complement-mediated lysis, respectively. Blue triangles, immune suppressive factors. B) Antigen-antibody complexes interact with C1q and result in formation of C1 complex, which then further activates the complement cascade by generating C3 convertase. C3 convertase recruits C3 and forms the C5 convertase. C5 convertase culminates in formation of the membrane attack complex (MAC) after recruiting other factors (C5b-C9). Formation of MAC results in compliment-mediated cell lysis. SCs inhibit activation of the complement cascade by expressing/secreting inhibitors (red boxes) which prevents the C1 complex, C3 convertase, C5 convertase and MAC formation.