Immune Regulation in the Male Genital Tract

Abstract

Spermatozoa are not produced until puberty, long after the establishment of tolerance to self-antigens. Therefore, sperm-specific antigens are immunogenic in men. Most men, however, do not produce antibodies to their own gametes. Development of mechanisms to prevent or limit autoimmune responses to spermatozoa were essential for preservation of reproductive capacity. Tight junctions between adjacent Sertoli cells, as part of the blood-testis barrier, prevent sperm-immune cell contact. In some portions of the genital tract this barrier is thin or incomplete. Immune mechanisms have evolved to actively suppress the autoimmune response to spermatozoa within the genital tract. Unlike in the circulation where CD4+ helper T lymphocytes predominate, CD8+ suppressor/cytotoxic T lymphocytes are the most prominant T cells in the epididymis and vas deferens. In addition, spermatozoa suppress pro-inflammatory lymphocyte immune responses, possibly by inducing production of anti-inflammatory cytokines. Antisperm antibody production is induced in the male genital tract when a local infection or disruption in the genital tract physical barrier leads to an influx of CD4+ T cells. In response to induction of a productive immune response, two additional mechanisms downregulate humoral immunity within the genital tract. T lymphocytes possessing the γσ form of the antigen receptor (γσ T cells) are concentrated in the male genital tract and in semen. These cells become activated and proliferate in men with evidence of sperm autoimmunity. Activated γσ T cells inhibit production of antibodies by activated B lymphocytes, thereby limiting antisperm antibody production. Heat shock proteins (hsps) are also present in semen in association with infection and antisperm antibody formation. Hsp gene transcription leads to inhibition of transcription of the genes coding for pro-inflammatory cytokines and, conversely, to activation of γσ T cells. Activated γσ T cells also promote hsp synthesis. The mechanisms to inhibit immunity to sperm may hinder effective immune elimination of microoganisms in the male genital tract.