Sperm proteins and cancer‐testis antigens are released by the seminiferous tubules in mice and men

O’Donnell, Liza; Rebourcet, Diane; Dagley, Laura F.; Sgaier, Raouda; Infusini, Giuseppe; O’Shaughnessy, Peter J.; Chalmel, Frédéric; Fietz, Daniela; Weidner, W.; Legrand, Julien M. D.; Hobbs, Robin M.; McLachlan, Robert I; Webb, Andrew I.; Pilatz, Adrian; Diemer, Thorsten; Smith, Lee B.; Stanton, Peter G.

doi:10.1096/fj.202002484r

Cited by 16 publications

(33 citation statements)

References 84 publications

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“…Tregs control tolerogenic versus autoimmune responses, with respect to sperm/testicular-specific antigens, as was demonstrated by Wheeler [122,151]. Vasectomy is a well-established form of birth control that does not lead to autoimmune orchitis, due to the presence of tolerogenic Tregs that are responsive to sperm/testicular-specific antigens [122,151,152]. Following vasectomy, the maintenance of tolerance toward sperm/testicular antigens leaking from the severed vas deferens requires a rapid response by Tregs [122,151,152].…”

Section: Appendix Amentioning

confidence: 91%

“…This can occur spontaneously in patients with AIRE gene mutations, due to dysfunctional Tregs [150]. Tregs control tolerogenic versus autoimmune responses, with respect to sperm/testicular-specific antigens, as was demonstrated by Wheeler [122,151]. Vasectomy is a well-established form of birth control that does not lead to autoimmune orchitis, due to the presence of tolerogenic Tregs that are responsive to sperm/testicular-specific antigens [122,151,152].…”

Section: Appendix Amentioning

confidence: 95%

“…Vasectomy is a well-established form of birth control that does not lead to autoimmune orchitis, due to the presence of tolerogenic Tregs that are responsive to sperm/testicular-specific antigens [122,151,152]. Following vasectomy, the maintenance of tolerance toward sperm/testicular antigens leaking from the severed vas deferens requires a rapid response by Tregs [122,151,152]. The Tregs arrest the elevation of auto-antibodies and pathogenic CD4 + T cells.…”

Section: Appendix Amentioning

confidence: 99%

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Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Sharpe

Baskin

Jenson

et al. 2021

IJMS

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Regulatory T-cells (Tregs) are immunosuppressive T-cells, which arrest immune responses to ‘Self’ tissues. Some immunosuppressive Tregs that recognize seminal epitopes suppress immune responses to the proteins in semen, in both men and women. We postulated that GBMs express reproductive-associated proteins to manipulate reproductive Tregs and to gain immune privilege. We analyzed four GBM transcriptome databases representing ≈900 tumors for hypoxia-responsive Tregs, steroidogenic pathways, and sperm/testicular and placenta-specific genes, stratifying tumors by expression. In silico analysis suggested that the presence of reproductive-associated Tregs in GBM tumors was associated with worse patient outcomes. These tumors have an androgenic signature, express male-specific antigens, and attract reproductive-associated Related Orphan Receptor C (RORC)-Treg immunosuppressive cells. GBM patient sera were interrogated for the presence of anti-sperm/testicular antibodies, along with age-matched controls, utilizing monkey testicle sections. GBM patient serum contained anti-sperm/testicular antibodies at levels > six-fold that of controls. Myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are associated with estrogenic tumors which appear to mimic placental tissue. We demonstrate that RORC-Tregs drive poor patient outcome, and Treg infiltration correlates strongly with androgen levels. Androgens support GBM expression of sperm/testicular proteins allowing Tregs from the patient’s reproductive system to infiltrate the tumor. In contrast, estrogen appears responsible for MDSC/TAM immunosuppression.

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Section: Appendix Amentioning

confidence: 91%

Section: Appendix Amentioning

confidence: 95%

Section: Appendix Amentioning

confidence: 99%

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Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Sharpe

Baskin

Jenson

et al. 2021

IJMS

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“…The differential sequestration status between LDH3 and ZAN is confirmed recently based on proteomic and mass spectroscopic analyses of the testis interstitial fluids and serum proteins ( 47 ). The authors proposed two hypothetical mechanisms for meiotic Ag egress from the ST. One is via the RB at stage IX of the spermatogenic cycle ( 25 ) and the second to occur earlier, at spermatogenic cycle stages VI and VII prior to RB formation.…”

Section: Resultsmentioning

confidence: 71%

Exposed and Sequestered Antigens in Testes and Their Protection by Regulatory T Cell-Dependent Systemic Tolerance

et al. 2022

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Continuous exposure of tissue antigen (Ag) to the autoantigen-specific regulatory T cells (Treg) is required to maintain Treg-dependent systemic tolerance. Thus, testis autoantigens, previously considered as sequestered, may not be protected by systemic tolerance. We now document that the complete testis antigen sequestration is not valid. The haploid sperm Ag lactate dehydrogenase 3 (LDH3) is continuously exposed and not sequestered. It enters the residual body (RB) to egress from the seminiferous tubules and interact with circulating antibody (Ab). Some LDH3 also remains inside the sperm cytoplasmic droplets (CD). Treg-depletion in the DEREG mice that express diphtheria toxin receptor on the Foxp3 promoter results in spontaneous experimental autoimmune orchitis (EAO) and Ab to LDH3. Unlike the wild-type male mice, mice deficient in LDH3 (wild-type female or LDH3 NULL males) respond vigorously to LDH3 immunization. However, partial Treg depletion elevated the wild-type male LDH3 responses to the level of normal females. In contrast to LDH3, zonadhesin (ZAN) in the sperm acrosome displays properties of a sequestered Ag. However, when ZAN and other sperm Ag are exposed by vasectomy, they rapidly induce testis Ag-specific tolerance, which is terminated by partial Treg-depletion, leading to bilateral EAO and ZAN Ab response. We conclude that some testis/sperm Ag are normally exposed because of the unique testicular anatomy and physiology. The exposed Ag: 1) maintain normal Treg-dependent systemic tolerance, and 2) are pathogenic and serve as target Ag to initiate EAO. Unexpectedly, the sequestered Ags, normally non-tolerogenic, can orchestrate de novo Treg-dependent, systemic tolerance when exposed in vasectomy.

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“…In fact, a proportion of meiotic germ cells antigens egress from the seminiferous tubules into the interstitium and maintain regulatory T (Treg; CD4 + /Foxp3 + ) cells dependent systemic tolerance [8]. Further, certain sperm-specific proteins are selectively released by the Sertoli cells in the testicular interstitial fluid which can be accessed by the immune system [9]. These studies have challenged the conventional belief that all antigens on the developing germ cells are uniformly sequestered from the immune system and suggest operation of additional mechanisms to maintain systemic tolerance.…”

Section: Structural Component Of Testis Blood-testis Barriermentioning

confidence: 99%

Immunoregulation in the testis and its implication in fertility and infections

2021

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The testis is designated as one of the immune previleged sites in the body and harbours a unique immunoregulatory environment, which is important for preventing an immune response against sperm antigens which otherwise are recognized as “foreign” by the immune system. The blood-testis barrier along with the unique immune cells repertoire and various immunoregulatory & immunosuppressive factors secreted by the Leydig cells, Sertoli cells and peritubular cells act in concert to maintain the tolerogenic environment in the testis. Abberations in immunotolerant mechanisms in the testis can lead to generation of anti-sperm antibodies that have an association with male infertility. It can also lead to inflammatory conditions of the male reproductive tract manifested as epididymitis and orchitis, generally due to bacterial or viral infections. In addition, non-infectious epididymitis and orchitis, having autoimmune origin have also been reported in males. While the immune privilege status of human testis protects the germ cells from an immune attack, it can also make the testis a succeptible reservoir for viruses such as human immunodeficiency virus-1, Zika virus and severe acute respiratory syndrome coronavirus-2, all of which have adverse consequences on male reproduction.

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Sperm proteins and cancer‐testis antigens are released by the seminiferous tubules in mice and men

Cited by 16 publications

References 84 publications

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Hijacking Sexual Immuno-Privilege in GBM—An Immuno-Evasion Strategy

Exposed and Sequestered Antigens in Testes and Their Protection by Regulatory T Cell-Dependent Systemic Tolerance

Immunoregulation in the testis and its implication in fertility and infections

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