DC belong along with macrophages to the most important antigen presenting cells (APC) and play a major role in the initiation and orchestration of primary immune responses. DC not only activate lymphocytes, but also tolerize T cells to antigens, thereby minimizing autoaggressive immune responses [44].

In normal mouse, rat, primate, and human, testis DC are found in very limited numbers [45–49]. In contrast, in the inflamed testis, the numbers of DC are significantly upregulated as shown in a rat model of experimentally induced autoimmune orchitis (EAO), where elevated levels of DC were found in the interstitial space of the testis and in testicular granulomas and lymph nodes draining the testis [46, 47, 50]. Similarly, in human azoospermic testis with chronic inflammation, higher numbers of IL-23 producing CD11c+ DC could be detected [49].

Immature DC have the highest capacity to internalize antigens, but low T cell stimulatory activity, whereas mature DC downregulate their endocytic activity and are excellent T lymphocyte stimulators [51]. Interestingly, the levels of co-stimulatory molecules (CD80, CD86) and MHC class II molecules on the DC surface from normal and inflamed rat testis are similar [46]. However, the expression of chemokine receptor CCR7 responsible for the migratory behavior to the lymph nodes was upregulated in DC from inflamed testis. Furthermore, the expression of IL-12p35 and IL-10 mRNA was detectable only in DC from EAO testis and draining lymph nodes pointing to their mature immunogenic state [46, 50]. At the functional level, DC isolated from EAO testis and draining lymph nodes significantly enhanced the proliferation of effector T cells compared with control DC, suggesting a more tolerogenic phenotype for DC in normal testis function, thereby maintaining immune privilege (Fig. 5.1) [46, 50]. Based on existing data, it seems that during development of testicular inflammation DC acquire a functional mature phenotype, take up testicular antigens, migrate to the lymph nodes, and stimulate antigen-specific T cell responses, thus initiating autoimmune responses in the testis leading to immunological infertility.

In normal testis of human and experimental animals, the population of lymphocytes comprises 10–20 % of total leukocytes. Testicular T cells consist mainly of CD4+, CD8+, and CD4+ CD25+ Foxp3+ regulatory (Treg) T cells [48, 52–54]. Immunosuppressive factors produced locally in the testis such as IL-10, TGF-β, activin A or lyso-glycerophosphocholine are believed to promote diminished responses of testicular T cells leading to prolonged tolerance [48, 55–57]. A hallmark of disturbed immunological balance during testicular inflammation is significantly increased numbers of CD4+ and CD8+ T cells as well as Treg cells [58–60]. There is increasing evidence that testicular CD4+ CD25+ Foxp3+ Treg are important players in the maintenance of testicular immune privilege. Interestingly, data from our own in vivo and in vitro studies showed a stimulatory effect of testosterone on the expansion of Treg cells in the testis [59, 61]. Moreover, factors produced by cultured Sertoli cells like TGF-β trigger de novo differentiation of fully functional Treg cells [62].

In addition to the well-established anabolic and spermatogenic effects, a role for androgens in downregulating pro-inflammatory responses has now been shown in both experimental and in clinical studies. Incubation of several immune and nonimmune cell types with testosterone resulted in the suppression of adhesion molecules and cytokines such as IL-1, IL-6, and TNFα and increased production of anti-inflammatory cytokines such as IL-10 [63–69]. Testosterone is also involved in T cell apoptosis [70]. A direct connection between sex steroid levels and testicular immune privilege was shown by Head and Billingham [71], when in transplantation studies, rats pretreated with estrogen to suppress Leydig cell testosterone production, promptly rejected intratesticular allografts in contrast to tolerance towards the grafts in untreated cohorts. In interventional studies, testosterone supplementation of hypogonadal patients with Crohn’s disease led to reduced protein C levels and inhibition of chronic inflammation [72, 73]. These findings were supported by evidence delivered from our earlier studies, showing that substitution of reduced testosterone levels during rat EAO inhibited the disease development and caused reduction of TNF-α, IL-6 and MCP-1 levels in testis. Furthermore, the number of TM and CD4+ T cells was significantly decreased with concomitant increase of Treg cells as compared to untreated EAO animals [59]. Further in vitro studies confirmed an inhibitory effect of testosterone on inflammatory responses in Sertoli and peritubular cells [61]. These studies indicate that the high local testosterone concentrations characteristic for the testis seem to play an important role in the maintenance of testicular immune privilege.

What can be surmised from the available data is that androgens appear to exert their immunosuppressive function on testicular leukocytes by stimulating the differentiation of Treg cells and by regulating the balance of pro- and anti-inflammatory cytokine expression in Sertoli, Leydig, and peritubular cells.

There is now widespread agreement that the immune system, spermatogenesis, and steroidogenesis, and the intrinsic testicular functions are intricately linked by a network of complex interactions. The importance of the delicate balance needed between the suppression of the immune response to protect the germ cells from autoattack on the one hand and the ability to an active immune response to prevent damage from infection, trauma, and cancer on the other is reflected by the fact that in the human male about 12–13 % of all diagnosed infertility is related to an immunological reason. It needs to be considered that the incidence can well be higher as the contribution to idiopathic infertility (31 % of all cases) still remains elusive [9–12]. The mechanisms responsible for testicular immune privilege are still far from being understood, but it is apparent that the identified factors involved are multiple. According to recent progress, androgens and possibly other steroid hormones are likely to play a major role [61, 74]. Overall, long regarded as a peculiar side issue of testis function, immune privilege is now established as part of the general scheme of male gamete formation and successful reproduction. Further research in the area will not only help to improve diagnosis and treatment of immunological based male infertility, but will also open new avenues in contraceptive development and transplantation medicine.