Sertoli Cell-Specific Deletion of the Androgen Receptor Compromises Testicular Immune Privilege in Mice1

Abstract

In the mammalian testis, meiotic and postmeiotic germ cell antigens are granted immune privilege. Both local immune suppression and specialized intercellular junctions between somatic Sertoli cells have been proposed to contribute to a highly restricted and effective blood-testis barrier (BTB) that helps maintain tolerance to germ cell antigens. Several studies have suggested that androgens play a role in immune suppression, although direct evidence for this is lacking. We previously reported that Sertoli cell-specific ablation of the androgen receptor (Ar) decreases expression of Cldn3, an androgen-regulated gene and component of Sertoli cell tight junctions, and increases the permeability of the BTB to biotin, a small-molecular-weight tracer. The physiological consequences of Sertoli cell-specific Ar (S-Ar) ablation on immune privilege are unknown. Here we show that in the testes of S-Ar mutant mice, the ultrastructure of Sertoli cell tight junctions is defective and testicular IgG levels are elevated. The interstitium of S-Ar mutant testes becomes populated with macrophages, neutrophils, plasma cells, and eosinophils, and serum samples of mutant mice contain antibodies against germ cell antigens. Together, these results suggest that Sertoli cell-specific deletion of the androgen receptor results in loss of testicular immune privilege. Suppressed levels of androgen signaling may be a contributing factor in idiopathic male infertility.

The Blood-Testis Barrier and Its Implications for Male Contraception

“…It is noted that the intratesticular testosterone level, such as in the seminiferous tubule fluid, is maintained at ϳ100 times the level found in the systemic circulation in both humans and rodents (10 Ϫ7 versus 10 Ϫ9 M) (Turner et al, 1984;Jarow and Zirkin, 2005) to sustain spermatogenesis. Earlier findings coupled with studies using transgenic mouse models have demonstrated that androgens are crucial in the regulation of almost every aspect of spermatogenesis, including spermatogonial proliferation and differentiation, germ cell cycle progression through meiosis, spermiogenesis, spermiation, and cell adhesion at the Sertoli-Sertoli and Sertoli-germ cell interface in the seminiferous epithelium Ruwanpura et al, 2010;Verhoeven et al, 2010;O'Donnell et al, 2011) and to confer immune privilege in the testis (Meng et al, 2011). These effects are mediated via androgen receptor (AR) using genomic and/or nongenomic pathways (Walker, 2009(Walker, , 2010Lamont and Tindall, 2010;Shupe et al, 2011).…”

Testicular defense systems: immune privilege and innate immunity

“…61 Androgens also regulate the testicular immunoprivileged status. [64][65][66] Notably, androgens would not directly affect testicular immune cells because these cells lack the androgen receptor.…”

“…Conditional knockout of the androgen receptor in SCs in mice impairs testicular immune privilege, possibly due to the impairment of BTB permeability. 65,71 Taken together, androgens would contribute to testicular immune privilege by negatively regulating the local immune responses and systemic tolerance to auto-antigens.…”

Sertoli cells – Immunological sentinels of spermatogenesis

“…An example of the immunological importance of the BTB/SC barrier in spermatogenesis was demonstrated in SC specific androgen receptor knock out mice (Ar-KO) [33]. In these mice, biotin was detected in the adluminal compartment indicating increased permeability of the BTB/SC barrier to small molecules.…”