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H-Y is a transplantation antigen that can lead to rejection of male organ and bone marrow grafts by female recipients, even if the donor and recipient match at the major histocompatibility locus of humans, the HLA (human leukocyte antigen) locus. However, the origin and function of H-Y antigens has eluded researchers for 40 years. One human H-Y antigen presented by HLA-B7 was identified as an 11-residue peptide derived from SMCY, an evolutionarily conserved protein encoded on the Y chromosome. The protein from the homologous gene on the X chromosome, SMCX, differs by two amino acid residues in the same region. The identification of H-Y may aid in transplantation prognosis, prenatal diagnosis, and fertilization strategies.

H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.

Sex difference is an established risk factor for hematopoietic stem cell transplantation (HSCT)-related complications like graft versus host disease (GVHD). CD8pos cytotoxic T cells specific for Y chromosome-encoded minor Histocompatibility antigens (HY) play an important role therein. Prior to HSC donation, female donors may encounter HY antigens through fetomaternal or transmaternal cell flow, potentially leading to the induction of HY-specific cytotoxic or regulatory immune responses. Whether HY priming occurs independent of parity, and whether HY priming is dependent on the presence of male microchimerism, is as yet unknown. We investigated the presence of HY-specific regulatory T cells (Treg) and male microchimerism in 45 healthy women with a fully documented pregnancy and family history. HY peptide-induced linked suppression, a commonly reported functional feature of CD4pos and CD8pos Treg, was measured by trans vivo Delayed Type Hypersensitivity testing. As source of HY antigens, male microchimerism was analyzed by real-time PCR and defined by the presence of male DNA in at least one purified leukocyte cell type. HLA class I or class II restricted HY-specific Treg were detected in 26/42 (62%) women eligible for analysis. The prevalence of HY-specific Treg was significantly higher in women who had never given birth to sons than in women with male offspring (p = 0.004). Male microchimerism could be detected in 24 out of 45 (53%) women but did not correlate with the presence of HY specific Treg. HY-specific Treg in women with male offspring have been described previously. Here we show for the first time that, in fact, HY specific Treg are more common in nulliparous women and in parous women with female offspring. Their presence is independent of the presence of male microchimerism. Whether HY-specific Treg presence in female stem cell grafts might decrease the GVHD incidence in male HSCT recipients needs to be investigated.

Bladder cancer is regarded as a promising candidate for innovative therapies in the field of immune and gene therapy. In this paper, we present the subcutaneous, metastatic and a novel orthotopic model of murine MB49 bladder cancer in C57BL/6 mice. We further show the potential of using adenoviral vectors together with different transduction enhancers to augment in vivo gene delivery. Finally, we present candidate genes for tumour detection, therapy or targeting. The MB49 tumour grew rapidly in mice. The subcutaneous model allowed for tumour detection within a week and the possibility to monitor growth rate on a day-by-day basis. Injection of MB49 cells intravenously into the tail vein gave rise to lung metastases within 16 days, while instillation of tumour cells into pretreated bladders led to a survival time of 20-40 days. Adenoviral vectors can be used as a vehicle for gene transfer to the bladder. By far, the most potent transduction enhancer was Clorpactin, also known as oxychlorosene. Last, we show that MB49 cells express tumour-associated antigens like bladder cancer-4, prostate stem cell antigen and six-transmembrane epithelial antigen of the prostate. Given the possibility for efficient genetic modification of the bladder and the presence of known tumour antigens, the MB49 models can be used in innovative ways to explore immunogene therapy.

The requisite molecular interactions for CD8 T cell memory were determined by comparison of monoclonal naive and memory CD8$^+$ T cells bearing the T cell receptor (TCR) for the HY antigen. Naive T cells required only the right major histocompatibility complex (MHC) class I-restricting molecule to survive; to expand, they also needed antigen. In contrast, for survival, memory cells did not require the restricting MHC allele, but needed only a nonspecific class I; for expansion the correct class I, but not antigen, was required. Thus, maintenance of CD8 T cell memory still required TCR-MHC class I interactions, but memory T cells may have a lower functional activation threshold that facilitates secondary responses.

Minor histocompatibility (H) antigens can be peptides derived from cellular proteins that are presented on the cell surface by major histocompatibility complex (MHC) class I molecules. This is similar to viral antigens, because in both cases cytotoxic T lymphocytes (CTLs) recognize artificially produced peptides loaded on target cells. Naturally processed minor H peptides were found to be similar to those artificial CTL-epitopes, as far as size and hydrophobicity is concerned. The peptides studied were isolated from a transfectant that expressed a model CTL-defined antigen, β-galactosidase, from male cells that express H-Y, which has been known operationally since 1955, and from cells that express H-4, known since 1961.

A fetus is inherently antigenic to its mother and yet is not rejected. The T regulatory (Treg) subset of CD4⁺ T cells can limit immune responses and has been implicated in maternal tolerance of the fetus. Using virgin inbred mice undergoing a first syngenic pregnancy, in which only the male fetuses are antigenic, we demonstrate a maternal splenocyte proliferative response to the CD4⁺ T cell restricted epitope of the male antigen (H-Y) in proportion to the fetal antigen load. A portion of the maternal immune response to fetal antigens is Treg in nature. The bystander suppressive function of pregnancy-generated Tregs requires the presence of the fetal antigen, demonstrating their inherent antigen specificity. In vivo targeting of diphtheria toxin to kill Tregs leads to a lower fraction of live male offspring and a selective reduction in mass of the surviving males. Thus, Tregs generated in the context of pregnancy function in an antigen-specific manner to limit the maternal immune response to the fetus in a successful pregnancy.

Genetic sex-determining mechanisms have been extensively elucidated in mammals; however, the sex chromosomes, sex-determining genes, and gene regulatory networks involved in sex differentiation remain poorly understood in amphibians. In this study, we investigated the sex-determining mechanism in the Hyla eximia treefrog based on karyotypic analysis and identification of H-Y antigen, a sex-linked peptide that is present in the gonads of the heterogametic sex (XY or ZW) in all vertebrates. Results show a diploid chromosome number 2n = 24 with homomorphic sex chromosomes. The heterogametic sex, ZW-female, were hypothesized based on H-Y antigen mRNA expression in female gonads (24,ZZ/24,ZW). The treefrog H-Y peptide exhibited a high percentage of identity with other vertebrate sequences uploaded to GenBank database. To obtain gene expression profiles, we also obtained the coding sequence of the housekeeping Actb gene. High H-Y antigen expression levels were further confirmed in ovaries using real-time polymerase chain reaction (RT-PCR) during non-breeding season, we noted a decrease in the expression of the H-Y antigen during breeding season. This study provides evidence that sex hormones might suppress H-Y antigen expression in the gonads of heterogametic females 24,ZW during the breeding season. These findings suggest that H-Y gene expression is a well-suited model for studying heterogametic sex by comparing the male and female gonads.

The male-specific minor histocompatibility antigen H-Y plays an important role in both graft rejection and graft-versus-host disease following transplantation of male tissue into females that are completely matched at the major histocompatibility loci. The recent identification of two peptides that, in association with the mouse H-2Kk or human HLA B7 major histocompatibility class I molecules, are recognised by H-Y-specific T cells, has provided evidence for the molecular basis for such anti-H-Y responses. These peptides are encoded by the mouse and human homologues of a ubiquitously expressed Y chromosome gene, Smcy, whilst the equivalent peptides encoded by the X chromosome homologues of this gene fail to be recognised. Genetic studies have demonstrated that, as is the case for other minor histocompatibility antigens, peptide epitopes from several closely linked genes may be required to interact in order to elicit a response against H-Y. Definition of the peptides and the genes that encode these epitopes will allow the development of tolerogenic protocols that could specifically down-modulate the response to H-Y and perhaps even other minor histocompatibility antigens.

THE male-specific transplantation antigen, H-Y, causes rejection of male tissue grafts by genotv pically identical female mice 1 and contributes to the rejection of human leukocyte antigen-matched male organ grafts by human females 2 . Although first recognized 40 years ago 1 , the identity of H-Y has remained elusive. T cells detect several distinct H-Y epitopes 3–5 , and these are probably peptides, derived from intracellular proteins, that are presented at the cell surface with major histocompatibility complex (MHC) molecules 6 . In the mouse, the gene(s) controlling H-Y expression ( Hya ) are located on the short arm of the Y chromosome 7,8 between the zinc-finger genes Zfy-1 and Zfy-2 (ref. 9). We have recently identified Smcy a ubiquitously expressed gene, in this region 10 and its X-chromosome homologue, Smcx 11 . Here we report that Smcy encodes an H-YK k epitope that is defined by the octamer peptide TENSGKDI: no similar peptide is found in Smcx . These findings provide a genetic basis for the antigenic difference between males and females that contributes towards a tissue transplant rejection response.