T Lymphocytes and Testicular Immunity: A New Insight into Immune Regulation in Testes

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.

Keywords: Leydig cells; Sertoli cells; cytotoxic T cells; helper T cells; natural killer T cells; regulatory T cells; spermatogenesis; γδ T cells.

Figure 1

Balance between Treg cells and Teff cells in the testes. Under normal conditions, Tregs could effectively control Teff cells through several immunosuppressive mechanisms, and a balance between them could instrumentally sustain and foster normal spermatogenesis and testicular homeostasis. However, Treg cells are outnumbered by vigorously expanding Teff cells under pathological states, such as testicular chronic inflammation and infection, and the balance between Treg and Teff cells is disturbed, resulting in impaired spermatogenesis, autoimmune orchitis, and/or azoospermia. DC, dendritic cell; HSP, heat shock protein; IL, interleukin; IDO, indoleamine 2,3-dioxygenase; Mφ, macrophage; Treg, regulatory T cell; Teff, effective T cell; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; Upward arrow: detectable increase of cytokine level; Dotted line: proposed communication among cells.

Figure 2

Hypothetical schematic model of testicular immune privilege under normal (A) and inflammatory (B) conditions. A: Under normal conditions, Th cells are tightly controlled by Tregs through multiple mechanisms. B: In the presence of chronic testicular inflammation, resulting from a temporary or silent infection, necrosis of testicular cells can lead to the release of self-antigens (e.g., HSP, ODF-2), peptides, and/or of pathogen-associated molecular patterns, i.e., LPS, which can enhance the maturation and population of antigen-presenting cells and Mø in the testes, thus further activating Th17 cells and triggering autoimmunity. CTL, cytotoxic T lymphocytes; DC, dendritic cell; GC, germ cell; HSP, heat shock protein; IDO, indoleamine 2,3-dioxygenase; T, testosterone; CCL, chemokine ligand; FasL, Fas ligand; IL, interleukin; IFN-γ, interferon; LC, Leydig cell; Mø, macrophage; ODF-2, outer dense fiber protein 2; PTC, peritubular cell; SC, Sertoli cell; TGF-β, transforming growth factor β; TNF-α, tumor necrosis factor α; Th, T helper cell; Treg cell, regulatory T cell.