MALE GENITAL TRACT IMMUNITY chains (/8 T cells) have been found to be concen- trated in human semen 16’17. Unlike in the circulation where y8 T cells were less than 10% of the total T lymphocyte population, in semen they comprised 33-50% of the T cells. A greatly elevated seminal y8 T cell concentration was consistently observed in men with sperm autoimmunity or immunological evidence of a genital tract Chlamydia trachomatis infection. /8 T cells are also present in the genital tracts of male mice where they have been shown to prevent pro-inflammatory immune resonses to sperm-specific antigens 18. Similarly, y8 T cells limit both destructive immune responses during experi- mental infection 19 and maternal anti-fetal immunity during pregnancyz. The mechanism of y8 T cell immune suppres- sion may involve the synthesis by these cells of anti- inflammatory cytokinesz’z. Alternatively, resting y T cells can be stimulated by activated antibody- producing B lymphocytes, but not by resting B cells. Once activated, y8 T cells actively suppress the release of IgG from the B cell surfacezz. Thus, the concentration of y8 T cells in the male genital tract provides another mechanism to downregulate im- mune responses at that site. HEAT SHOCK PROTEINS In response to immune activation and the release of pro-inflammatory cytokines the genes coding for heat shock proteins are transcribed23. Extracellular phospholipase A2 activity, an early consequence of microbial infection, also induces heat shock protein biosynthesis24. Heat shock proteins prevent intra- cellular protein degradation and incorrect polypep- tide assembly when the cell encounters conditions unfavorable to its survival. In addition, initiation of heat shock protein gene transcription inhibits transcription of the macrophage genes coding for interleukin-1 (IL-1) and tumor necrosis factor-or (TNFot)23,2s,26. Thus, up-regulation of heat shock protein synthesis is another means of down-regulat- ing pro-inflammatory immune responses. The 60kD heat shock protein has been identi- fied in semen samples from some men with im- munological evidence of a chlamydial infection or sperm autoimmunity but not in semen from men lacking evidence of local immune activation27. This suggests that heat shock protein gene re- sponses may be operational within the male gen- ital tract. The ability of y8 T cells to initiate WITKIN ET AL. heat shock protein gene expression28 and, in turn to be activated by heat shock protein29, coupled with the observed association between seminal y8 T cell concentration and genital tract immune activation6,17, reinforces the plausibility of this mechanism. REGULATION OF IMMUNE RESPONSES IN THE MALE GENITAL TRACT. Based on the experimental evidence cited above, we propose the following mechanism of immune regulation in the male genital tract (Fig. 1). In the case of men with neither sperm autoimmunity nor a genital tract infection, contact between spermato- zoa and T cells and macrophages does not lead to a pro-inflammatory immune response. IFNy is not being produced due to the lack of immune stimula- tion. MHC class 2 expression on macrophages is, therefore, not induced. Concurrently, spermatozoa induce the production of anti-inflammatory cyto- kines. Therefore, genital tract immunity is down- regulated. Conversely, however, in men with pre- existing sperm autoimmunity or a current genital tract infection, activation of CD4+ otl3 T cells in- duces the release of IFNy. This activates macro- phages to engulf spermatozoa, transport spermato- zoal antigens to the macrophage surface in association with newly expressed MHC class 2 mol- ecules. The activated macrophage also releases the pro-inflammatory cytokines IL-1 and TNF-ot This overwhelms the pre-existing immune suppression and B lymphocytes are activated to produce anti- bodies to spermatozoal and microbial antigens. Should a pro-inflammatory immune response be initiated its magnitude is down-regulated at discreet stages by the mechanisms also shown in Fig. 1. Pro-inflammatory cytokine synthesis initiates heat shock protein gene transcription. Concomitantly, antibody-producing activated B cells stimulate the proliferation of y8 T cells. Heat shock protein also stimulates y8 T cells activation and vice versa. The activated y8 T cells then inhibit further antibody production while heat shock protein gene transcrip- tion inhibits further transcription of inflammatory cytokine genes. An intriguing question still open to speculation is whether the capacity of some men to effectively combat infections at this site is impaired by the evolution of these mechanisms which limit sperm autoimmunity in the genital tract, or by differences INFECTIOUS DISEASES IN OBSTETRICS AND GYNECOLOGY 133