Dual role of immune cells in the testis: Protective or pathogenic for germ cells?

Abstract

The purpose of this review is to describe how the immune cells present in the testis interact with the germinal epithelium contributing to survival or apoptosis of germ cells (GCs). Physiologically, the immunosuppressor testicular microenvironment protects GCs from immune attack, whereas in inflammatory conditions, tolerance is disrupted and immune cells and their mediators respond to GC self antigens, inducing damage of the germinal epithelium. Considering that experimental models of autoimmune orchitis have clarified the local immune mechanisms by which protection of the testis is compromised, we described the following topics in the testis of normal and orchitic rats: (1) cell adhesion molecule expression of seminiferous tubule specialized junctions and modulation of blood-testis barrier permeability by cytokines (2) phenotypic and functional characteristics of testicular dendritic cells, macrophages, effector and regulatory T cells and mast cells and (3) effects of pro-inflammatory cytokines (TNF-α, IL-6 and FasL) and the nitric oxide-nitric oxide synthase system on GC apoptosis.

Keywords: blood-testis barrier; cytokines; germ cell apoptosis; immune cells; inflammation; nitric oxide; seminiferous tubules; testis.

Figure 1. Schematic drawing illustrating the seminiferous epithelium and intestitium under normal (A) or inflammatory (B) conditions. (A) The seminiferous epithelium is composed of Sertoli cells and germ cells at different stages of development. The blood-testis barrier (BTB) is constituted by coexisting adherens, gap and tight junctions between adjacent Sertoli cells. As representative tight junction molecules, occludin and ZO-1 are shown. Macrophages close to Leydig cells and few immature dendritic cells (DCs), T cells and regulatory T cells (Treg) are present in the interstitium. (B) Spermatocytes and spermatids undergo apoptosis and sloughing in the lumen of the seminiferous tubule. Decreased occludin expression in Sertoli cell tight junctions associated to impairment of BTB is shown. An increased number of mature DCs, pro-inflammatory and intermediate type macrophages, CD4+ and CD8+ T cells and T regs are present in the interstitium. Pro-inflammatory cytokines (IL-6, TNF-α, FasL, IFN-γ, IL-17) and nitric oxide (NO) released by macrophages and T cells are involved in the induction of inflammation and germ cell apoptosis. Cytokines and other factors secreted by Sertoli, Leydig and peritubular cells are not illustrated.