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. 2011 Aug;85(2):254-60.
doi: 10.1095/biolreprod.110.090621. Epub 2011 May 4.

Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice

Jing Meng  1 , Anne R Greenlee, Chloe J Taub, Robert E Braun
Affiliations

Sertoli cell-specific deletion of the androgen receptor compromises testicular immune privilege in mice

Jing Meng et al. Biol Reprod. 2011 Aug.

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.

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Figures

FIG. 1
FIG. 1
Altered ultrastructure of tight junctions in S-Ar mutant testes. Electron micrographs of WT and S-Ar mutant seminiferous epithelium. A) WT seminiferous tubule. Boxed region contains a tight junction formed between the two adjacent Sertoli cells. B) Higher magnification of the boxed region in A. Arrows indicate regions of close apposition of Sertoli cell lipid bilayers (kissing points). C) Seminiferous tubule of an S-Ar mutant. Boxed region shows the intercellular space of two neighboring Sertoli cells. D) High magnification of the boxed region in C. Note the absence of kissing points between the membranes of the adjacent Sertoli cells (arrow heads). SC, Sertoli cells. Bar in A = 2 μm for A and C; bar in B = 200 nm for B and D.
FIG. 2
FIG. 2
Loss of androgen signaling in Sertoli cells induces a humoral autoimmune response. A) Western blot analysis of extracts prepared from the testes of WT and S-Ar mice probed with a mouse anti-β-catenin antibody. β-catenin served as a loading control. Higher concentrations of IgG heavy and light chains were evident in the mutant testicular extract. B) Western blot analysis of extracts prepared from the testes of WT mice probed with sera from WT and S-Ar and ArTfm mutant mice. A portion of the gel was stained with Coomassie blue to demonstrate equal loading. Arrows indicate 70- and 130-kDa testicular antigens recognized by antibodies present in serum samples from two different S-Ar mutant males.
FIG. 3
FIG. 3
Autoantigens emerge with development of haploid spermatids. A) Western blot analysis of total testis protein prepared from juvenile male mice on PN Days 5–40 and (top) probed with serum from an S-Ar mutant male or (bottom) serum from a WT control male. A portion of the gel was stained with Coomassie blue to demonstrate equal loading of samples. B) Immunofluorescence detection of self-antigens in WT testis sections. Serum sample from a WT male mouse (I). Sera from two different S-Ar mutant males (S-Ar 1 and S-Ar 2, II–IV). Serum antibodies from the S-Ar 3 mutant male recognize antigens associated with basal germ cells (IV). Bar = 20 μm (applies to all panels). Insets show 2× enlargements of highlighted regions.
FIG. 4
FIG. 4
Inflammatory cells infiltrate the testes of S-Ar mutant mice. A) Flow cytometric analysis of whole testicular cell suspensions from WT and mutant mice show significantly higher percentages of CD11B-positive macrophages, neutrophils, and eosinophils and CD3-positive T lymphocytes in S-Ar mutant mice (both n = 4). An unstained control was used to exclude negative testicular cells and set gates for the CD11B and CD3 populations. B) Immunohistochemistry of macrophages stained with F4/80 antibody. Positive cells are stained red in the interstitium of WT and S-Ar mutant testes and noted with arrows. Bar = 20 μm (applies to both images). C) In comparison to WT, percentages of CD138(+) plasma cells in whole blood, testicular intersitium, and seminiferous tubules were significantly higher in S-Ar mutant mice (all n = 3). D) In comparison to WT, the interstitia of S-Ar mutants contained significantly higher percentages of CD11B(+) cells. It was possible to subdivide the CD11B-positive population into neutrophils, monocytes, and eosinophils based on costaining with anti-GR-1 antibody and by side scatter to detect granularity (all n = 3). *P < 0.05; **P < 0.01.
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