Macrophages and dendritic cells in the post-testicular environment

Abstract

Macrophages (MΦ) and dendritic cells (DCs) are heterogeneous families of functionally and developmentally related immune cells that play crucial roles in tissue homeostasis and the regulation of immune responses. During the past 5 years, immunologists have generated a considerable amount of data that challenge dogmas about the ontogeny and functions of these highly versatile cells. The male excurrent duct system plays a critical role in the establishment of fertility by allowing sperm maturation, transport and storage. In addition, it is challenged by pathogens and must establish a protective and tolerogenic environment for a continuous flow of autoantigenic spermatozoa. The post-testicular environment and, in particular, the epididymis contain an intricate network of DCs and MΦ; however, the immunophysiology of this intriguing and highly specialized mucosal system is poorly understood. This review summarizes the current trends in mouse MΦ and DC biology and speculates about their roles in the steady-state epididymis. Unraveling immune cell functions in the male reproductive tract is an essential prerequisite for the design of innovative strategies aimed at controlling male fertility and treating infertility.

Keywords: Antigen-presenting cells; Dendritic cells; Epididymis; Macrophages; Peripheral tolerance; Sperm maturation; Spermatozoa.

Figure 1. Simplified classification of mouse mononuclear phagocytes based on their ontogeny

According to recent fate mapping studies, most tissue-resident macrophages (Mϕ) arise from erythro-myeloid progenitors (EMPs) in the embryo. They self-renew in adult tissues independently of hematopoietic stem cells (HSCs). In contrast, dendritic cell (DC) subsets originate from a common DC precursor (CDP) that derives from HSCs in the bone marrow. CDPs progressively differentiate to give rise to pre-DCs and, ultimately, classical DCs (cDCs) and plasmacytoid DCs (pDCs). In the steady state intestine, and following inflammation, circulating monocytes differentiate into monocyte-derived DCs (moDCs) and macrophages (mo Mϕ). Therefore, most peripheral organs are populated by various subsets of Mϕ and DCs with distinct origins and phenotypes. Ultimately, tissue mononuclear phagocytes are shaped by their microenvironment in order to exert organ-specific functions. Currently, the ontogeny of epididymal DCs and Mϕ is unknown.

Figure 2. The blood-epididymis barrier is surveyed by mononuclear phagocytes

The main component of the epididymis is a long tube lined by a pseudostratified epithelium that contains several cell types connected by apical tight junctions (TJs). ZO-1 immunolabeling (red, panel A) reveals the TJ network. Nuclei were labeled with DAPI (blue). This tight epithelium constitutes a physical barrier between the luminal compartment and the rest of the body, named the blood-epididymis barrier. The tubule is also populated by mononuclear phagocytes that closely interact with neighboring epithelial cells. Panel B shows a cross section of the mouse epididymal duct in the initial segment. Sperm are visible in the lumen. Cells that express green fluorescent protein under the control of CX3CR1 promoter are shown in pseudocolor to enhance contrast. CX3CR1 is expressed by subsets of monocytes, macrophages and dendritic cells. In the epididymis, CX3CR1⁺ cells are embedded in the epithelium, but are also present in the peritubular region and in the interstitium (arrowheads). Bars = 20 μm. (L): lumen.

Figure 3. Possible roles of macrophages and dendritic cells in the epididymis

Mononuclear phagocytes (MPs) are show in green in this schematic depiction of a cross section of the mouse epididymal duct. DCs and Mϕ express various levels of leukocyte surface markers and exhibit distinct morphological characteristics. In the proximal epididymis, a subset of CX3CR1⁺ CD11c⁺ cells establishes close interactions with neighboring epithelial cells. These intraepithelial Mϕ maintain the blood-epididymis barrier by rapidly removing apoptotic cells and debris (1). In addition, they project dendritic processes toward apical tight junctions and occasionally reach the luminal compartment. Such a mechanism could allow Mϕ and DCs to directly or indirectly acquire luminal antigens, including sperm antigens and pathogens, to initiate immune defense or tolerance (2). While intraepithelial macrophages are stationary, CD103⁺ DCs migrate into lymph nodes following antigen acquisition. Furthermore, the proximal epididymis interstitium contains a dense network of capillaries; fenestrated capillaries of the initial segments may be monitored by neighboring MPs (3). In the gut, a crosstalk between macrophages and neurons is involved in the regulation of intestinal motility; similarly, macrophages may regulate the contraction of peritubular smooth muscle cells in the epididymis (4).