Abstract
The immune privilege of the testes is necessary to prevent immune attacks to gamete-specific antigens and paternal major histocompatibility complex (MHC) antigens, allowing for normal spermatogenesis. However, infection and inflammation of the male genital tract can break the immune tolerance and represent a significant cause of male infertility. Different T cell subsets have been identified in mammalian testes, which may be involved in the maintenance of immune tolerance and pathogenic immune responses in testicular infection and inflammation. We reviewed the evidence in the published literature on different T subtypes (regulatory T cells, helper T cells, cytotoxic T cells, γδ T cells, and natural killer T cells) in human and animal testes that support their regulatory roles in infertility and the orchitis pathology. While many in vitro studies have indicated the regulation potential of functional T cell subsets and their possible interaction with Sertoli cells, Leydig cells, and spermatogenesis, both under physiological and pathological processes, there have been no in situ studies to date. Nevertheless, the normal distribution and function of T cell subsets are essential for the immune privilege of the testes and intact spermatogenesis, and T cell-mediated immune response drives testicular inflammation. The distinct function of different T cell subsets in testicular homeostasis and the orchitis pathology suggests a considerable potential of targeting specific T cell subsets for therapies targeting chronic orchitis and immune infertility.
Highlights
Mammalian spermatogenesis starts from undifferentiated spermatogonia, which undergo reduction division, forming spermatozoa
The publications reviewed in the present study show the subtle equilibrium between immune privilege and inflammation inside the testes
T lymphocytes play an imperative role in testis immunity and orchestrate other immune cells and stromal cells inside the testes, maintaining a tolerance status in terms of the physiological condition and arousing an immune response under threat of infection and tumorigenesis (Table 1)
Summary
Mammalian spermatogenesis starts from undifferentiated spermatogonia, which undergo reduction division, forming spermatozoa. The blood–testis barrier (BTB) mainly consists of Sertoli cells (SCs), which form a physical shield for sperm that circumvents the immune cells and provide a protective biochemical environment [2] While this physical barrier efficiently prevents the immune–sperm cell contact, other immune mechanisms are required to inhibit the potential autoimmune response, especially at some joints where the dam is frail or missing, such as the tubuli recti and rete testis. These mechanisms include a diminished reactivity of resident macrophages to inflammation, inhibited proinflammatory cytokines, tolerogenic cytokines induced by androgens, anti-inflammatory cytokines expressed by regulatory immune cells and somatic cells, antigen-specific immune suppression by dendritic cells, and quiescent mast cells [3]. While these cells only account for the minority, for example, 10–20% of total immune cells in adult rat testes under physiological conditions [11], they are essential for the maintenance of immune homeostasis and are involved in the pathogenesis of male infertility [12]
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