Manifestations of immune tolerance in the human female reproductive tract

Abstract

Like other mucosal surfaces (e.g., the gastrointestinal tract, the respiratory tract), the human female reproductive tract acts as an initial barrier to foreign antigens. In this role, the epithelial surface and subepithelial immune cells must balance protection against pathogenic insults against harmful inflammatory reactions and acceptance of particular foreign antigens. Two common examples of these acceptable foreign antigens are the fetal allograft and human semen/sperm. Both are purposely deposited into the female genital tract and appropriate immunologic response to these non-self antigens is essential to the survival of the species. In light of the weight of this task, it is not surprising that multiple, redundant and overlapping mechanisms are involved. For instance, cells at the immunologic interface between self (female reproductive tract epithelium) and non-self (placental trophoblast cells or human sperm) express glycosylation patterns that mimic those on many metastatic cancer cells and successful pathogens. The cytokine/chemokine milieu at this interface is altered through endocrine and immunologic mechanisms to favor tolerance of non-self. The "foreign" cells themselves also play an integral role in their own immunologic acceptance, since sperm and placental trophoblast cells are unusual and unique in their antigen presenting molecule expression patterns. Here, we will discuss these and other mechanisms that allow the human female reproductive tract to perform this delicate and indispensible balancing act.

Keywords: cervix; human; immune privilege; semen; trophoblast; vagina.

Figure 1

Carbohydrate sequences involved in immune privilege in the human reproductive system. N-glycans usually have two (biantennary), three (triantennary), or four (tetraantennary) antennae linked at up to four positions (designated A–D). On the human ZP, there are biantennary and triantennary N-glycans terminated on every antenna with the SLEX sequences on every antenna (Pang et al., 2011). Tetraantennary N-glycans bearing three SLEX antenna are also present. Human sperm and seminal plasma express bi-, tri-, and tetra-antennary N-glycans terminated exclusively with Lewis^x or exclusively with Lewis^y sequences on their antennae, though many carry a mixture of both of these sequences (Pang et al., 2007, 2009). Glycodelin-A bears the fucosylated lacdiNAc sequence on 60% of its total N-glycans (Dell et al., 1995). Uromodulin expresses one (UM-1), two (UM-2), or three SLEX sequences on a single O-glycan (Easton et al., 2000). These types of presentations have not been found in other normal cells or tissues outside of the human reproductive system.

Figure 2

Human placental structure (after 12 weeks of gestation): the human placenta has a fetal and a maternal side. The fetal side consists of a mass of tree-like villous structures that are bathed in maternal blood. Unlike floating villae, anchoring villae traverse the blood-filled intervillous space and attach to the maternal decidualized endometrium. The maternal decidua is populated by stromal and immune cells and is crossed by spiral arteries that dump blood into the intervillous space. Floating and anchoring placental villae are coated by an inner layer of individual, fetally-derived cytotrophoblast (Cyto-T) cells and an outer layer of fused syncytiotrophoblast (Syn-T) cells. A third population of fetally-derived trophoblast cells arises from Cyto-T at the tips of anchoring villae. These extravilous cytotrophoblast (EVTB) cells invade deeply into the maternal tissues and remodel maternal spiral arteries.

Figure 3

HLA-G: the most common form of the non-classical MHC class Ib molecule, HLA-G, mimics HLA-A and -B in structure and is called HLA-G1. HLA-A, -B and -G1 are all homodimers of an MHC class I heavy chain comprised of five domains and a stabilizing second molecule, beta-2 microglobulin (β₂m). The MHC class I heavy chain consists of an α1 and α2 domain (forming the antigenic peptide-binding groove), an α3 domain, a transmembrane domain and a cytopalasmic tail. Unlike classical MHC class I molecules, the cytoplasmic tail of HLA-G is very short, containing only six amino acids. Also unlike classical MHC class Ia molecules, HLA-G can be detected as several spliced variants. The most common of these are the membrane-bound HLA-G1, -G2, -G3 and -G4 and the soluble HLA-G5, -G6 and -G7. Soluble forms have lost their transmembrane segments and cytoplasmic tails during splicing.