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Of vessels and cells: the spatial organization of the epididymal immune system

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REVIEW ARTICLE

Correspondence:

Jo€el R. Drevet and Rachel Guiton, GReD laboratory, 28 place Henri Dunant 63001 Clermont-Ferrand Cedex, France.

E-mails: joel.drevet@uca.fr (J. R. D.); rachel.guiton@uca.fr (R. G.)

*These authors contributed equally to this work. Keywords:

blood vessels, epididymis, immune cells, lymphatic vessels

Received: 15-Nov-2018 Revised: 14-Mar-2019 Accepted: 1-Apr-2019

doi: 10.1111/andr.12637

Of vessels and cells: the spatial

organization of the epididymal

immune system

R. Guiton

,

*A. Voisin, *J. Henry-Berger, F. Saez

and J. R. Drevet

GReD laboratory,CNRS, UMR 6293– INSERM U1103 – Clermont Auvergne University, Clermont-Ferrand, France

ABSTRACT

Background: One third of infertility cases in couples worldwide has an exclusive male origin and immune disorders, essentially due to repetitive infections, are emerging an cause of male infertility. As the place of sperm maturation, epididymis must be pre-served from excessive immune responses that may arise following infections of the male genital tract. At the same time, epididymis must set and maintain a tolerogenic environment in order not to destroy sperm cells that enter the tissue at puberty, long after the immune system has been taught to recognize self pathogens. The immune cells that populate the epididymis have raised growing interest over the last thirty years but they may be not sufficient to understand the immune balance existing in this organ, between immune response to pathogens and tolerance to spermatozoa. Indeed, immune cells are the most motile cells in the organism and need blood and lymphatic vessels to traffic between lymphoid organs and sites of infection to induce efficient responses.

Objectives: To review the literature on the blood and lymphatic vessels, and on the immune cells present at steady state in the rodent epididymis (rat and mouse).

Materials and methods: PubMed database was searched for studies reporting on the spatial organization of the rodent epididymal vasculature and immune cell types at steady state. This search was combined with recent findings from our team.

Results: At steady state, the rodent epididymis presents with dense blood and lymphatic networks, and a large panel of immune cells distributed across the interstitum and epithelium along the organ.

Conclusions: The immune system of the rodent epididymis is highly organized. Exploring its functions, especially in an infectious context, is the essential coming step before any transposition to human.

INTRODUCTION

One couple out of six is affected by infertility worldwide, and one-third of these cases has an exclusive male origin. Interest-ingly, up to 15% of male infertilities are due to immune disor-ders, mainly consecutive to infections or autoimmune reactions, and this may be underestimated as idiopathic cases account for 30–40% of male infertility cases (Haidl et al., 2008; Jungwirth et al., 2012). Studies dedicated to the male reproductive tract immunity are mainly focused on the testis which is obviously crucial for fertility. However, spermatozoa are only able to fertil-ize the oocyte after their maturation in the epididymis, which clearly underlines a critical role for the epididymis as well. As so, many works have focused on the epididymal immune system, with a special emphasis on the defense molecules and immune

cells that populate the tissue (Hall et al., 2002; Com et al., 2003; Malm et al., 2005; Britan et al., 2006; Palladino et al., 2007, 2008; Collin et al., 2008; Linge et al., 2008; Da Silva et al., 2011; Jrad-Lamine et al., 2011, 2013; Ribeiro et al., 2016; Voisin et al., 2018). Moreover, the epididymal epithelial cells also seem to play a role in the organ defense (Zhu et al., 2015; Cheng et al., ; Browne et al., 2018).

Nonetheless, the immune system is not restricted to cells and molecules. It is a complex organization which also encompasses lymphoid organs and vessels. Classically, professional antigen-presenting cells (APCs) capture antigens in peripheral organs and migrate to secondary lymphoid organs (spleen and lymph nodes) through blood or lymphatic vessels. Then, APCs present the antigens to na€ıve T cells that become activated and return to

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the tissue where the antigen was encountered, through the lym-phatic system. T cells generally enter secondary lymphoid organs via specialized blood vessels (Owen et al., 2013). Thus, blood vessels as well as lymphatic vessels appear crucial for the traffic of APCs and T cells, and thus for the initiation of immune responses.

This review summarizes the current knowledge on two aspects of the epididymal immune system that are under investigation in our research team: the blood and lymphatic epididymal cir-cuitry, and the immune cells, with a special focus on their spatial organization in the rodents which may help to consider their contributions in maintaining the unique epididymal immune environment.

VASCULARIZATION

Most of the studies available on the epididymal vasculariza-tion are focused on blood vessels that populate the tissue. They describe two types of vasculature: the gross vasculature that sur-rounds the epididymis and the microvasculature that deeply penetrates the tissue.

The gross vasculature of rodent epididymis

As described in the early 1980s, the proximal part of the mur-ine epididymis is supplied by two branches of the testicular artery. The upper one enters the epididymis at the connective tissue septum that divides the initial segment from the rest of the caput epididymis, while the lower artery joins the organ on the surface of the central part of the corpus epididymis. The dis-tal part of the organ is supplied by the deferential artery (Suzuki, 1982; Abe et al., 1984). Unfortunately, the gross vasculature of the rat epididymis is not published but the blood microvascula-ture has been studied and, as such, will be mentioned in the fol-lowing sections (Markey & Meyer, 1992).

Contrary to the blood vasculature, the gross lymphatic drai-nage of the epididymis has only been published in the rat. Using India ink and radiopaques, Perez-Clavier et al. (1982) showed that most of the lymphatic vessels came from the caput, one or two from the corpus, and only one from the cauda epididymis. Moreover, the collecting vessels generally followed the blood supply and gathered to form a single vessel that joined the main testicular lymphatic trunk. This scheme was largely confirmed by McDonald and Scothorne (McDonald & Scothorne, 1988). These two studies also identified the regional testicular lymph node as being the epididymal draining lymph node in the rat.

In our team, we took advantage of a transgenic mouse model allowing a fluorescent visualization of the lymphatic vessels (Calvo et al., 2011). We mainly showed that the lymphatic collector ves-sels follow the epididymal septa (manuscript in preparation).

The blood microvasculature in rodent epididymis The initial segment

Kormano was the first to describe tortuous capillaries sur-rounding the tubules of the rat epididymis, forming a dense net-work in the initial segment, while subepithelial capillaries were never described (Kormano, 1968). This was later confirmed by a study showing that the highest percentage of interstitial capillar-ies, around 5%, was found in that region compared to the rest of the caput, the corpus, and the cauda epididymis (Markey & Meyer, 1992).

In the mouse epididymis, the dense capillary network in the initial segment was first reported by the use of India ink perfu-sion (Takano, 1980). Interconnections were frequently seen between peritubular capillaries in mice using a casting method coupled with scanning electron microscopy (Suzuki, 1982), and it was also observed by light microscopy on thick sections of the tissue where narrow meshes elongated in the transverse direc-tion of the duct were noted (Abe et al., 1984). Peritubular capil-laries were observed into the muscular layer as well as at the subepithelial layer level of each tubule in the initial segment (Suzuki, 1982). These capillaries were fenestrated, contrary to the capillaries of the other segments (Abe et al., 1983, 1984). The subepithelial capillaries had pores of 60 nm in diameter, more frequent on the epithelial side of the vessel (Abe et al., 1984). The interstitium showed less capillaries than the subepithelial compartment but presented larger vessels of the non-fenestrated type (Suzuki, 1982; Abe et al., 1984). However, a common prob-lem for the oldest studies in the field was to discriminate between blood and lymphatic vessels. A study took advantage of technical breakthroughs and used markers specific for each type of vessels, that are CD31 (platelet endothelial cell adhesion molecule, also known as PECAM1) for the blood vessels and LYVE-1 (lymph vessel endothelium HA-receptor 1) for the lym-phatic vessels (Hirai et al., 2010). They definitely confirmed the abundance of blood capillaries in the initial segment of the mouse epididymis as they occupy 1.08% of the epididymal initial segment tissue surface. This percentage raises to 10.26% in the epididymal interstitium (Table 1). Moreover, this study con-firmed that the initial segment is the only one to contain blood capillaries just beneath the basal lamina.

The blood capillary structure and abundance in the initial seg-ment of rodents is suggested to be closely related to the special function of this segment, that is, the reabsorption of the testicu-lar fluid by the epithelial cells (Levine & Marsh, 1971; Suzuki, 1982; Turner, 1984).

The caput and corpus epididymis

In the rat epididymis, the number of capillaries dramatically decreased from the initial segment to the rest of the caput and to the corpus epididymis (Markey & Meyer, 1992). Moreover, the corpus epididymis interstitium showed capillaries that pene-trated the smooth muscle layer to form a subepithelial capillary network (Kormano, 1968).

This decreased capillary density was also reported in the mouse epididymis where a coarse network was observed at the end of the caput and in the corpus epididymis (Suzuki, 1982; Abe

Table 1 Percentages illustrating the tissue surface occupied by blood and lymphatic capillaries in the murine epididymal segments

I. S. caput corpus cauda Blood capillaries

Capillary area/epididymal tissue (%)a 1.08 0.54 0.54 1.04

Capillary area/epididymal interstitium (%)b 10.26 5.79 5.73 9.39

Lymphatic capillaries

Capillary area/epididymal tissue (%)a 0.07 0.3 0.29 0.53

Capillary area/epididymal interstitium (%)b 0.69 3.17 2.85 4.92

The data were extracted from Hirai et al. (2010).aArea of blood or lymphatic

cap-illary lumina/area of epididymal tissue (including epididymal ducts)9 100.bArea

of blood or lymphatic capillary lumina/area of epididymal interstitium (i.e., out-side the basal lamina of epididymal ducts)9 100.

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et al., 1984). Indeed, capillaries of low diameter were parallel to the tubules to form intertubular vessels interconnected by the peritubular capillaries. The blood vessels generally did not pene-trate into the smooth muscle layer surrounding the tubules (Suzuki, 1982). Contrary to the initial segment, few subepithelial capillaries were found, usually in the smooth muscle layer, and they were of the non-fenestrated type. The interstitial capillaries were similar to those of the initial segment (Abe et al., 1984). The cauda epididymis

In the rat epididymis, the capillary size (average luminal sur-face density of capillaries, lm2/lm3) decreased by 23% from the initial segment to the cauda region and the interstitial capillaries decreased by 52% in the same direction (Markey & Meyer, 1992). As for the corpus epididymis, the interstitial capillary network penetrated the smooth muscle layer that surrounded the tubules of the cauda epididymis (Kormano, 1968), and the percentage of the smooth muscle capillaries was similar between the corpus and cauda epididymis. As the number of muscular capillaries increased with the thickness of the muscular layer, it was sug-gested that these vessels may not be involved in the epithelial function but may rather have a role in the maintenance and con-trol of the smooth muscle wall (Markey & Meyer, 1992).

In the mouse cauda epididymis, blood capillaries were abun-dant and peritubular capillaries entered the subepithelial layer to encircle the tubules (Suzuki, 1982; Hirai et al., 2010), and this organization was similar to that of the initial segment. There was an increase in the capillary density from the proximal to the dis-tal cauda region. The caudal network architecture is suggested to fit the high requirement for blood supply to support the increased caliber of the tubule (Suzuki, 1982).

The lymph microvasculature in rodent epididymis

To our knowledge, only one study focused on the lymph microvasculature of the mouse epididymis in addition to the two studies describing the gross lymphatic vasculature in the rat (Perez-Clavier et al., 1982; McDonald & Scothorne, 1988; Hirai et al., 2010). A general observation was that the lymphatic net-work was scarce in the initial segment of the mouse epididymis compared to the other regions, and especially to the cauda epi-didymis (Table 1). Hirai and colleagues also reported lymphatic sinusoid-like structures around the blood capillaries in the initial segment but these were different from the cauda ones. The lym-phatic capillaries area was significantly lower in the initial seg-ment than in the caput and corpus epididymis, while there was no difference between these two compartments. Finally, the lymphatic capillaries area was significantly higher in the cauda epididymis than in the caput and corpus regions. An interesting observation pointed to an area ratio of blood/lymphatic capillar-ies of approximately two through the caput, corpus, and cauda epididymis, while this ratio was around 16 in the initial segment (Hirai et al., 2010). However, results from our laboratory, using three-dimensional reconstruction of the murine epididymis after whole mount stainings against lymphatic and blood markers, seem to contradict this vision that was obtained through less powerful methods using immunohistochemical stainings of tis-sue sections (manuscript in preparation). Indeed, we observed a very dense lymphatic microvasculature around the organ as well as around each epididymal tubule.

IMMUNE CELLS

The immune cells populating the rodent epididymis have long been studied. The first studies focused on macrophages, B cells, and conventional ab T lymphocytes (i.e., CD4+ and CD8+) (Nashan et al., 1989; Hooper et al., 1995; Flickinger et al., 1997; Serre & Robaire, 1999). Over the last 20 years, the knowledge on the populations of immune cells has considerably been improved and the immune system now appears much more complex than it used to. Thus, recent works deepened the previ-ous studies, with a particular emphasis on mononuclear phago-cytes and lymphophago-cytes present at steady state. Unfortunately, only a few studies described the polymorphonuclear cells in the steady state rodent epididymis, despite their crucial role in the early steps of the pathogen recognition that initiate the immune response (Fritz & Pabst, 1989; Gaytan et al., 1989; Majeed, 1994a,1994b; Hess, 1998; Serre & Robaire, 1998; Mendes et al., 2011; Ogo et al., 2018).

The mononuclear phagocytes in rodent epididymis

The mononuclear phagocytes comprise three populations of immune cells: the monocytes and dendritic cells, and the macro-phages (Guilliams et al., 2014). All are pivotal to the innate immunity, the monocytes as stress sensors and the macrophages and dendritic cells as antigen-presenting cells. The three popula-tions were found in the rodent epididymis but their proper local-ization is complicated by their expression of redundant markers, especially in the mouse (Guilliams et al., 2014). All the cells localized in the works presented thereafter are reported accord-ing to the authors’ designation, and thus must be taken with care as their nature will need to be confirmed using combinations of cell-specific markers. However, one constant data are their absence from the tubular lumen.

The macrophages

Immunostaining on rat epididymal sections revealed that macrophages were more present in the interstitium than in the epithelium, throughout the organ. In fact, macrophages were almost absent from the epithelium (Flickinger et al., 1997). These results were in accordance with those from a previous study that used another marker of macrophages and a different rat strain (Hooper et al., 1995). A third study definitely con-firmed the presence of macrophages in every segment of the rat epididymis (Serre & Robaire, 1999). Moreover, these cells were frequently located in the lower half of the epithelium, close to the basement membrane. The number of macrophages increased with age in the initial segment, caput, and corpus epi-didymis, and in old rats, the proximal cauda epididymis showed an increased number of macrophages. Age also influenced the size of epithelial macrophages, as young rats mainly showed small cells, while older animals showed a significant increase in large macrophages in the initial segment, caput, and corpus epi-didymis, and later in the proximal cauda epididymis. In contrast, neither the number nor the size of macrophages were affected by age in the distal cauda epididymis. Moreover, the number and the size of interstitial macrophages located close to the epi-didymal tubule were not affected by age.

In the murine epididymis, macrophages were more repre-sented than lymphocytes in the caput, corpus, and cauda com-partments. An important part of these cells, almost 30%, were

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found in the peritubular area throughout the organ, while only 13% were located in the interstitium and 1% in the epithelium of the caput and corpus epididymis (Nashan et al., 1989). Using a more recent and accurate technology, that is flow cytometry, we confirmed in the murine epididymis at steady state the highest concentration of macrophages compared to other immune cell types and demonstrated that they were more numerous in the caput than in the cauda compartment (Voisin et al., 2018). The dendritic cells

Dendritic cells were described in the murine epididymis (Da Silva et al., 2011). Indeed, a dense network of peritubular CD11c-YFP+and CX3CR1-GFP+cells, originally called eDCs

(epi-didymal dendritic cells), was found in the corresponding trans-genic mouse models. In the proximal epididymis, eDCs project dendrites between epithelial cells and some have been shown to cross the tight junctions to reach the lumen. In the distal parts of the organ, eDCs lost their intraepithelial extensions but kept their interaction with the basal surface of the epithelium. Some intraepithelial eDCs were occasionally detected in addition to their preferential peritubular location. This study, as the previ-ous ones, relied on a unique marker to identify cell types, which is now known not to be sufficient (Guilliams et al., 2014). The authors thus deepened their work by using complex combina-tions of markers and identified distinct populacombina-tions of mononu-clear phagocytes. Dendritic cells appeared to be mainly located at the peritubular level, while macrophages essentially popu-lated the epididymal interstitium (Da Silva et al., 2011). Our recent flow cytometry study confirmed the presence of three populations of conventional dendritic cells and showed that all were more numerous in the caput than in the cauda epididymis (Voisin et al., 2018). We did not find any plasmacytoid dendritic cell in the tissue at steady state, which was quite expected as they are mainly involved in the antiviral response (Asselin-Paturel et al., 2001). Unfortunately, we were unable to localize both macrophages and dendritic cells as there were too numer-ous markers needed to proceed to immunostaining.

The monocytes

This last mononuclear phagocyte population has only been identified once in the murine epididymis (Voisin et al., 2018). They can be divided into classical and non-classical monocytes. Both populations were almost absent from the tissue at steady state which was not surprising as they are mainly implicated in stress sensing, being recruited to inflamed tissues where they differentiate into inflammatory dendritic cells or macrophages to sustain the local action of antigen-presenting cells (Mildner et al., 2016).

The lymphocytes in rodent epididymis

Among the lymphocytes, many populations exist such as B cells, NK and NKT cells, and conventional ab T cells and uncon-ventional T cells. Some of them have been described in the mur-ine epididymis in the late eighties, while others have only been identified recently (Da Silva et al., 2011; Voisin et al., 2018). As for the mononuclear phagocytes, none of the lymphocytes were present in the tubular lumen at steady state.

The CD4+helper lymphocytes

The CD4+T lymphocytes appeared more numerous than the CD8+ T lymphocytes through the four regions of the rat

epididymis: initial segment, caput, proximal cauda, and distal cauda. CD4+leukocytes were preferentially located in the inter-stitial compartment compared to the epithelium in the caput epididymis (Hooper et al., 1995; Flickinger et al., 1997). Their location in the subsequent segments of the organ is more con-troversial, as one study found them in much greater concentra-tion in the interstitium (Hooper et al., 1995), while the other one did not show any significant difference between epithelial and interstitial cells (Flickinger et al., 1997). A follow-up study indi-cated that the number of interstitial CD4+ T cells was not affected by age, except in the distal cauda epididymis where their number raised in older animals (Serre & Robaire, 1999). This study used a different rat strain and showed that intraep-ithelial CD4+ T lymphocytes were small round cells usually located close to the basal membrane, and occasionally at the apical point of tight junctions between principal cells. Their number increased in every region of aging animals, except in the caput epididymis.

CD4+ T lymphocytes were also equally described throughout the mouse epididymis, from the caput to the cauda regions. They were shown to have a preferential location in the intersti-tium and were rarely detected in the epithelium (Nashan et al., 1989; Voisin et al., 2018). These cells, also known as helper T cells, have been suggested to play a crucial role to sustain the immune response to epididymal pathogens (Voisin et al., 2019). Moreover, due to the particular need for a strong immune toler-ance to spermatozoa in the tissue, the regulatory T cells were studied in several works. Indeed, this subtype of CD4+T lympho-cytes is a well-known tolerance inducer. In a surprising way, they were almost or totally absent from the steady state murine epi-didymis, suggesting the presence of alternative mechanisms to maintain the local tolerance (Pierucci-Alves et al., 2018; Voisin et al., 2018).

The CD8+cytotoxic lymphocytes

The CD8+ T lymphocytes were more present in the intersti-tium than in the epithelium in the caput and proximal cauda of the rat epididymis (Hooper et al., 1995; Flickinger et al., 1997). Age influenced the total number of CD8+T cells in the organ as it was found significantly increased in all regions in old animals compared to young ones. However, the number of intertubular CD8+T cells was not affected by age in any segment, except in the corpus where they were significantly more numerous in old rats than in young animals (Serre & Robaire, 1999). The intraep-ithelial CD8+ T lymphocytes were small round cells found throughout the organ. They were found at various heights between epithelial cells but, as the CD4+T cells, were preferen-tially located in the basal region than in more apical locations where they were stopped at the tight junction level (Flickinger et al., 1997; Serre & Robaire, 1999).

All regions of the murine epididymis showed an equal per-centage of CD8+T lymphocytes, and these cells were distributed similarly between the interstitium, peritubular layer, and epithe-lium. Moreover, the percentages of CD4+and CD8+T cells were similar in the organ (Nashan et al., 1989). By quantifying the immune cells by flow cytometry, we confirmed the equal distri-bution of the CD8+T cells between the caput and cauda regions (Voisin et al., 2018). Given their distribution and their cytotoxic activity, they were proposed to participate in the pathogen elimi-nation in case of epididymal infection (Voisin et al., 2019).

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The unconventional T lymphocytes

In addition to the conventional CD4+ and CD8+ T lympho-cytes, unconventional populations do exist. Among them, the cd T cells that are typical mucosal lymphocytes were studied in the murine epididymis (Voisin et al., 2018). We found that they were equally distributed along the organ (caput vs. cauda epididymis) and immunofluorescent stainings revealed that they were mainly interstitial, with some intraepithelial cells. Given their role in other organs, they were suggested to participate to the pathogen clearance and/or to the anti-tumoral immunity (Bon-neville et al., 2010; Silva-Santos et al., 2015; Voisin et al., 2019).

The double-negative T (DN T) cells represent another popula-tion of unconvenpopula-tional T lymphocytes as these T cells lack the expression of both conventional ab T cell co-receptors, that is the CD4 and the CD8 molecules. The DN T cells were found more numerous in the caput than in the cauda epididymis and were more frequently observed in the interstitium than in the epithelium (Voisin et al., 2018). Based on experimental data, these cells were suggested to be involved in the anti-tumoral immunity as well as in the maintenance of the immune toler-ance that both take place in the murine epididymis (Young et al., 2003; Hillhouse & Lesage, 2013; Lee et al., 2018; Voisin et al., 2019).

The NK and NKT cells

Natural Killer (NK) and Natural Killer T (NKT) cells are crucial lymphocytes of the innate immunity. Their well-described anti-tumoral actions made them interesting populations to monitor in the epididymis, an organ with a particularly low tumoral inci-dence (Yeung et al., 2012). Surprisingly, none of them was found in the steady state murine epididymis (Voisin et al., 2018), sug-gesting the implication of other cell types in the anti-tumoral immunity as mentioned above.

The B lymphocytes

The first published study did not detect any B lymphocyte in the rat epididymis whatever the region or the compartment (ep-ithelium or interstitium) (Flickinger et al., 1997). The second work available only detected few cells in the epididymal epithe-lium of young rats, which represented <1% of immune cells. Their number raised to 5% of immune cells in older animals. They were described as small round cells often located close to the base of the epithelium (Serre & Robaire, 1999).

In the mouse epididymis, we found that B lymphocytes were more numerous in the cauda than in the caput region and mainly located in the interstitium even if some cells were observed in the peritubular layer (Voisin et al., 2018). They were suggested to produce the high amount of local interstitial IgAs which could limit the dissemination of interstitial pathogens (Voisin et al., 2019).

CONCLUSION

It is obvious that the literature currently available treated the vascularization apart from the immune cells that actually popu-late the rodent epididymis at steady state. Some crucial points are still to decipher as to the true role(s) of the immune cells pre-sent in the epididymis and their potential traffic in the organism by the blood and lymphatic vessels that have been described in the tissue. This is an important aspect as the accumulation of

immunocompetent cells, that is cytotoxic CD8+and helper CD4+ T cells, was often seen at the periphery, close to the blood or lymphatic vessels (Serre & Robaire, 1999). This will be possible in animal models of epididymitis.

In addition, the discoveries made in the rodent epididymis will have to face the human reality. Indeed, the initial segment which shows very interesting specificities in terms of cells and vessels does not exist as such in human. However, the distribution of the vessels in the mouse is similar to that in humans in the other regions and many functional equivalences between mouse and human immune cells have been discovered, especially among the various antigen-presenting cell populations (Suzuki, 1982; Suzuki & Nagano, 1986; Crozat et al., 2010;). Hence, when the roles of murine immune cells are known in the epididymis, it will undoubtedly be a solid basis for human studies.

ACKNOWLEDGEMENTS

Allison Voisin was supported by the French Ministry of Higher Education and Research (MESR). Our research team received financial support from INSERM, CNRS and UCA.

CONFLICT OF INTEREST

The authors declare no conflict of interest to disclose.

REFERENCES

Abe K, Takano H & Ito T. (1983) Ultrastructure of the mouse epididymal duct with special reference to the regional differences of the principal cells. Arch Histol Jpn 46, 51–68.

Abe K, Takano H & Ito T. (1984) Microvasculature of the mouse epididymis, with special reference to fenestrated capillaries localized in the initial segment. Anat Rec 209, 209–218.

Asselin-Paturel C, Boonstra A, Dalod M, Durand I, Yessaad N, Dezutter-Dambuyant C, Vicari A, O’Garra A, Biron C, Briere F & Trinchieri G. (2001) Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat Immunol 2, 1144–1150.

Bonneville M, O’Brien RL & Born WK. (2010) Gammadelta T cell effector functions: a blend of innate programming and acquired plasticity. Nat Rev Immunol 10, 467–478.

Britan A, Maffre V, Tone S & Drevet JR. (2006) Quantitative and spatial differences in the expression of tryptophan-metabolizing enzymes in mouse epididymis. Cell Tissue Res 324, 301–310.

Browne JA, Leir SH, Eggener SE & Harris A. (2018) Region-specific innate antiviral responses of the human epididymis. Mol Cell Endocrinol 473, 72–78.

Calvo CF, Fontaine RH, Soueid J, Tammela T, Makinen T, Alfaro-Cervello C, Bonnaud F, Miguez A, Benhaim L, Xu Y, Barallobre MJ, Moutkine I, Lyytikk€a J, Tatlisumak T, Pytowski B, Zalc B, Richardson W, Kessaris N, Garcia-Verdugo JM, Alitalo K, Eichmann A & Thomas JL. (2011) Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis. Genes Dev 25, 831–844.

Cheng L, Chen Q, Zhu W, Wu H, Wang Q, Shi L, Zhao X & Han D (2016) Toll-like receptors 4 and 5 cooperatively initiate the innate immune responses to uropathogenic escherichia coli infection in mouse epididymal epithelial cells. Biol Reprod 58, 1–11.

Collin M, Linge HM, Bjartell A, Giwercman A, Malm J & Egesten A. (2008) Constitutive expression of the antibacterial CXC chemokine GCP-2/ CXCL6 by epithelial cells of the male reproductive tract. J Reprod Immunol 79, 37–43.

Com E, Bourgeon F, Evrard B, Ganz T, Colleu D, Jegou B & Pineau C. (2003) Expression of antimicrobial defensins in the male reproductive tract of rats, mice, and humans. Biol Reprod 68, 95–104.

Crozat K, Guiton R, Guilliams M, Henri S, Baranek T, Schwartz-Cornil I, Malissen B & Dalod M. (2010) Comparative genomics as a tool to

(6)

reveal functional equivalences between human and mouse dendritic cell subsets. Immunol Rev 234, 177–198.

Da Silva N, Cortez-Retamozo V, Reinecker HC, Wildgruber M, Hill E, Brown D, Swirski FK, Pittet MJ & Breton S. (2011) A dense network of dendritic cells populates the murine epididymis. Reproduction 141, 653–663.

Flickinger CJ, Bush LA, Howards SS & Herr JC. (1997) Distribution of leukocytes in the epithelium and interstitium of four regions of the Lewis rat epididymis. Anat Rec 248, 380–390.

Fritz FJ & Pabst R. (1989) Numbers and heterogeneity of mast cells in the male genital tract of the rat. Int Arch Allergy Appl Immunol 88, 360–362. Gaytan F, Carrera G, Pinilla L, Aguilar R & Bellido C. (1989) Mast cells in

the testis, epididymis and accessory glands of the rat: effects of neonatal steroid treatment. J Androl 10, 351–358.

Guilliams M, Ginhoux F, Jakubzick C, Naik SH, Onai N, Schraml BU, Segura E, Tussiwand R & Yona S. (2014) Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny. Nat Rev Immunol 14, 571–578.

Haidl G, Allam JP & Schuppe HC. (2008) Chronic epididymitis: impact on semen parameters and therapeutic options. Andrologia 40, 92–96. Hall SH, Hamil KG & French FS. (2002) Host defense proteins of the male

reproductive tract. J Androl 23, 585–597.

Hess RA. (1998) Effects of environmental toxicants on the efferent ducts, epididymis and fertility. J Reprod Fertil Suppl 53, 247–259.

Hillhouse EE & Lesage S. (2013) A comprehensive review of the

phenotype and function of antigen-specific immunoregulatory double negative T cells. J Autoimmun 40, 58–65.

Hirai S, Naito M, Terayama H, Ning Q, Miura M, Shirakami G & Itoh M. (2010) Difference in abundance of blood and lymphatic capillaries in the murine epididymis. Med Mol Morphol 43, 37–42.

Hooper P, Smythe E, Richards RC, Howard CV, Lynch RV & Lewis-Jones DI. (1995) Total number of immunocompetent cells in the normal rat epididymis and after vasectomy. J Reprod Fertil 104, 193–198. Jrad-Lamine A, Henry-Berger J, Gourbeyre P, Damon-Soubeyrand C,

Lenoir A, Combaret L, Saez F, Kocer A, Tone S, Fuchs D, Zhu W, Oefner PJ, Munn DH, Mellor AL, Gharbi N, Cadet R, Aitken RJ & Drevet JR. (2011) Deficient tryptophan catabolism along the kynurenine pathway reveals that the epididymis is in a unique tolerogenic state. J Biol Chem 286, 8030–8042.

Jrad-Lamine A, Henry-Berger J, Damon-Soubeyrand C, Saez F, Kocer A, Janny L, Pons-Rejraji H, Munn DH, Mellor AL, Gharbi N, Cadet R, Guiton R, Aitken RJ & Drevet JR. (2013) Indoleamine 2,3-dioxygenase 1 (ido1) is involved in the control of mouse caput epididymis immune environment. PLoS ONE 8, e66494.

Jungwirth A, Giwercman A, Tournaye H, Diemer T, Kopa Z, Dohle G, Krausz C & European Association of Urology Working Group on Male Infertility (2012) European association of urology guidelines on male infertility: the 2012 update. Eur Urol 62, 324–332.

Kormano M. (1968) Microvascular structure of the rat epididymis. Ann Med Exp Biol Fenn 46, 113–118.

Lee J, Minden MD, Chen WC, Streck E, Chen B, Kang H, Arruda A, Ly D, Der SD, Kang S, Achita P, D’Souza C, Li Y, Childs RW, Dick JE & Zhang L. (2018) Allogeneic human double negative T cells as a novel immunotherapy for acute myeloid leukemia and its underlying mechanisms. Clin Cancer Res 24, 370–382.

Levine N & Marsh DJ. (1971) Micropuncture studies of the

electrochemical aspects of fluid and electrolyte transport in individual seminiferous tubules, the epididymis and the vas deferens in rats. J Physiol 213, 557–570.

Linge HM, Collin M, Giwercman A, Malm J, Bjartell A & Egesten A. (2008) The antibacterial chemokine MIG/CXCL9 is constitutively expressed in epithelial cells of the male urogenital tract and is present in seminal plasma. J Interferon Cytokine Res 28, 191–196.

Majeed SK. (1994a) Mast cell distribution in rats. Arzneimittelforschung 44, 370–374.

Majeed SK. (1994b) Mast cell distribution in mice. Arzneimittelforschung 44, 1170–1173.

Malm J, Nordahl EA, Bjartell A, Sørensen OE, Frohm B, Dentener MA & Egesten A. (2005) Lipopolysaccharide-binding protein is produced in the epididymis and associated with spermatozoa and prostasomes. J Reprod Immunol 66, 33–43.

Markey CM & Meyer GT. (1992) A quantitative description of the epididymis and its microvasculature: an age-related study in the rat. J Anat 180(Pt 2), 255–262.

McDonald SW & Scothorne RJ. (1988) The lymphatic drainage of the epididymis and of the ductus deferens of the rat, with reference to the immune response to vasectomy. J Anat 158, 57–64.

Mendes LO, Amorim JPA, Teixeira GR, Chuffa LGA, Fioruci BA, Pimentel TA, de Mello W, Jr PC, Pereira S, Martinez M, Pinheiro PF, Oliani SM & Martinez FE. (2011) Mast cells and ethanol consumption: interactions in the prostate, epididymis and testis of UChB rats. Am J Reprod Immunol 66, 170–178.

Mildner A, Marinkovic G & Jung S( 2016) Murine monocytes: origins, subsets, fates, and functions. Microbiol Spectr 4(5), MCHD-0033-2016.

Nashan D, Malorny U, Sorg C, Cooper T & Nieschlag E. (1989) Immuno-competent cells in the murine epididymis. Int J Androl 12, 85–94. Ogo FM, de Lion Siervo GEM, Staurengo-Ferrari L, de Oliveira ML,

Luchetta NR, Vieira HR, Fattori V, Verri WA Jr, Scarano WR & Fernandes GSA. (2018) Bisphenol A exposure impairs epididymal development during the peripubertal period of rats: inflammatory profile and tissue changes. Basic Clin Pharmacol Toxicol 122, 262–270. Owen J, Punt J & Stranford S. (2013) Kuby immunology, 7th edn,

Macmillan Higher Education, Basingstoke, UK.

Palladino MA, Johnson TA, Gupta R, Chapman JL & Ojha P. (2007) Members of the Toll-like receptor family of innate immunity pattern-recognition receptors are abundant in the male rat reproductive tract. Biol Reprod 76, 958–964.

Palladino MA, Savarese MA, Chapman JL, Dughi MK & Plaska D. (2008) Localization of Toll-like receptors on epididymal epithelial cells and spermatozoa. Am J Reprod Immunol 60, 541–555.

Perez-Clavier R, Harrison RG & Macmillian EW. (1982) The pattern of the lymphatic drainage of the rat epididymis. J Anat 134, 667–675. Pierucci-Alves F, Midura-Kiela MT, Fleming SD, Schultz BD & Kiela PR(

2018) Transforming growth factor beta signaling in dendritic cells is required for immunotolerance to sperm in the epididymis. Front Immunol 9, 1882.

Ribeiro CM, Silva EJR, Hinton BT & Avellar MCW. (2016) b-defensins and the epididymis: contrasting influences of prenatal, postnatal, and adult scenarios. Asian J Androl 18, 323–328.

Serre V & Robaire B. (1998) Segment-specific morphological changes in aging Brown Norway rat epididymis. Biol Reprod 58, 497–513. Serre V & Robaire B. (1999) Distribution of immune cells in the

epididymis of the aging Brown Norway rat is segment-specific and related to the luminal content. Biol Reprod 61, 705–714.

Silva-Santos B, Serre K & Norell H. (2015) cd T cells in cancer. Nat Rev Immunol 15, 683–691.

Suzuki F. (1982) Microvasculature of the mouse testis and excurrent duct system. Am J Anat 163, 309–325.

Suzuki F & Nagano T. (1986) Microvasculature of the human testis and excurrent duct system. Resin-casting and scanning electron-microscopic studies. Cell Tissue Res 243, 79–89.

Takano H. (1980) Qualitative and quantitative histology and histogenesis of the mouse epididymis, with special reference on the regional difference. Acta Anat Nippon 55, 573–587.

Turner TT. (1984) Resorption versus secretion in the rat epididymis. J Reprod Fertil 72, 509–514.

Voisin A, Saez F, Drevet JR & Guiton R. (2019) The epididymal immune balance: a key to preserving male fertility. Asian J Androl. [Epub ahead of print].

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Voisin A, Whitfield M, Damon-Soubeyrand C, Goubely C, Henry-Berger J, Saez F, Kocer A, Drevet JR & Guiton R. (2018) Comprehensive overview of murine epididymal mononuclear phagocytes and lymphocytes: unexpected populations arise. J Reprod Immunol 126, 11–17. Yeung CH, Wang K & Cooper TG. (2012) Why are epididymal tumours so

rare? Asian J Androl 14, 465–475.

Young KJ, Kay LS, Phillips MJ & Zhang L. (2003) Antitumor activity mediated by double-negative T cells. Cancer Res 63, 8014–8021.

Zhu W, Zhao S, Liu Z, Cheng L, Wang Q, Yan K, Chen Q, Wu H & Han D. (2015) Pattern recognition receptor-initiated innate antiviral responses in mouse epididymal epithelial cells. J Immunol 194, 4825–4835.

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