Testicular immunity

Abstract

The testis is a unique environment where immune responses are suppressed to allow the development of sperm that possess autoimmunogenic antigens. There are several contributors responsible for testicular immune privilege, including the blood-testis barrier, testicular immune cells, immunomodulation by Sertoli cells, and high levels of steroid hormones. Despite multiple mechanisms in place to regulate the testicular immune environment, pathogens that disrupt testicular immunity can lead to long-term effects such as infertility. If testicular immunity is disturbed, autoimmune reactions can also occur, leading to aberrant immune cell infiltration and subsequent attack of autoimmunogenic germ cells. Here we discuss cellular and molecular factors underlying testicular immunity and how testicular infection or autoimmunity compromise immune privilege. We also describe infections and autoimmune diseases that impact the testis. Further research into testicular immunity will reveal how male fertility is maintained and will help update therapeutic strategies for infertility and other testicular disorders.

Keywords: Autoimmunity; Blood-testis barrier; Immune privilege; Infertility; Orchitis; Testicular immunity.

Fig. 1.. Signaling involved in BTB dynamics.

mTORC1 and mTORC2 encourage BTB remodeling and integrity, respectively. These can quickly regulate the opening and/or closure of the BTB throughout the microdomains of the BTB during the transit of preleptotene spermatocytes across the immunological barrier because of their antagonistic effects on one another. mTORC1 (a complex produced by mTOR and Raptor) influences the arrangement of actin and the relative stability of adhesion protein complexes at the BTB through rpS6; p-Akt1/2, which involves the Arp3 complex and its upstream activator N-WASP; and MMP9. mTORC2 (a complex produced by mTOR and Rictor) exerts its effect through gap junctions (GJ, such as Cx43-based GJ communication channels) and aPKC (atypical protein kinase C)/Rac1 GTPase. aPKC mediates actin reorganization and promotes GJ communication to coordinate basal ES, TJ, and desmosome functions. The phosphorylated/activated forms of FAK (p-FAK-Tyr407 and p-FAK-Tyr397) sustain BTB integrity and promote BTB remodeling, respectively. To facilitate the passage of preleptotene spermatocytes through the immunological barrier, these two signaling molecules function as molecular switches that can be used to turn the immune barrier on or off by making it tighter or leaky.

Fig. 2.. Downstream signaling cascades of the three endogenously produced biologically active peptides.

Matrix metalloproteases (MMPs) catalyze the proteolytic release of the three physiologically active peptides that regulate the structure and function of the BTB from structural elements of the apical ectoplasmic specialization (ES) and basement membrane. NC1 and LG3/4/5 peptides are generated at the basement membrane by MMP9-mediated proteolysis from collagen-α3 (IV) and laminin-α2, respectively. The apical ES undergoes MMP2-mediated proteolysis to create F5 peptide from laminin-γ3. Each of these peptides’ downstream signaling cascades is shown. The mTORC1/Akt/Cdc42 pathway is used by NC1 and LG3/4/5 peptides to regulate basal ES/BTB and apical ES function. In contrast, basal ES/BTB and apical ES remodeling/degeneration are regulated by the F5 peptide through the FAK/N–WASP/Arp2 pathway. BTB: Blood-testis barrier.

Fig. 3.. Immunoregulation in the testis.

Under homeostasis, testicular cells (comprised of germ, Sertoli, Leydig, peritubular myoid cells and immune cells) produce immunosuppressive factors to maintain an immune-privileged environment that supports the survival of germ cells. When the testis is infected by bacteria or viruses, the testis has the capability to initiate an inflammatory reaction through the induction of TLR signaling, production of pro-inflammatory factors, and the mobilization and stimulation of circulating immune cells, including monocytes and cytotoxic T lymphocytes. Chronic inflammatory stimulation will eventually result in BTB disruption and germ cell loss.

Fig. 4.. Testicular autoimmunity and infections.

Shown are immune responses associated with testicular health, contrasting autoimmune mechanisms versus infection-related impacts. On the autoimmune side, ASAs reduce sperm quality, driven by B cell activation against sperm-specific antigens. Autoimmune orchitis is driven by T cell activities such as cytokine production, immune cell recruitment, and B cell activation, leading to testicular damage. Testicular torsion leads to ischemia and ROS production, cytokine release, immune cell infiltration, and hypoxia. The immune response to torsion can result in damage to the contralateral (untwisted) testis due to the systemic nature of the immune response, and removal of the affected testis may be necessary if the damage is severe. Regarding infections, pathogens like HPV, MuV, ZIKV, and SARS-CoV-2 directly infect testicular tissue, while others indirectly influence testicular function, causing epididymitis, prostatitis, and urethritis. LCs: Leydig cells; T: testosterone; ECM: extracellular matrix; Mφ: macrophages; TPCs: testicular peritubular cells.