The H-Y antigen and sex reversal

Abstract

The search for molecules controlling sex determination in mammals has been, and continues to be, a field replete with controversy. At present, there are several key questions that remain to be answered: 1) What is the relationship between the different male-specific antigens that have been defined using different immunological criteria? 2) On which chromosome (chromosomes) do the genes for these male-specific antigens reside? and 3) Do the male-specific antigens that have been studied for so many years actually play a primary role in sex determination, or do they have other (secondary) roles in this process? Historical Perspective The male-specific antigen H-Y was first discovered in the 1950s as a transplantation antigen that caused female mice of certain inbred strains to reject male skin of their own strains. Subsequently, H-Y-specific T cell responses were generated in vitro, thus facilitating assays for the antigen (for review, see Simpson, Immunology Today 3, 97-106, 1982). In the early 1970s male-specific antibodies were detected in the serum of female mice grafted with male skin. These antibodies were assumed to be directed against the H-Y antigen defined previously by transplantation, although there was no direct evidence to support this. Wachtel et al. (Nature 757, 235-236, 1975) first proposed the idea that the serologically defined H-Y antigen might be the molecule responsible for triggering testis differentiation in the gonadal anlage in embryos. According to their hypothesis, any embryo expressing the (serologically defined) H-Y antigen and its receptor would develop a testis-which, under normal circumstances, is sufficient to induce differentiation of the male genital tract. In addition, their hypothesis predicted that all individuals with a testis would be positive for the (serologically defined) H-Y antigen. Silvers et al. (Cell 28,439-440, 1982) questioned the validity of the serological typing for the male-specific antigen (antigens) for several reasons, including the variable reproducibility of the test in different laboratories. Since there was little evidence that the serological entity was the male antigen, H-Y, defined as a transplantation antigen, they suggested that it be called SDM (serologically detectable male) antigen. Studies of individuals having a sex-reversed phenotype (i.e., XY females and XX males) provide a means to test the hypothesis that the H-Y antigen is necessary for male development. In all the sex-reversal studies discussed below, H-Y typing was done with T cells, since this assay is Minireview