NKR-P1+ Cells in the Rat Uterus: Granulated Metrial Gland Cells are of the Natural Killer Cell Lineage1

Abstract

An intriguing component of the maternal response to pregnancy is the differentiation of large numbers of large granular lymphocytes, termed granulated metrial gland (GMG) cells, in the decidua and then in the metrial gland, a structure in the mesometrial triangle unique to rodent pregnancy. We have used the monoclonal antibody 3.2.3 to NKR-P1, a surface molecule involved in triggering natural killer (NK) cells for lysis, to determine the numbers and distribution of NK cells in the nonpregnant rat uterus and during the dramatic changes at implant sites during pregnancy. NKR-P1+ cells were abundant in the nonpregnant uterus, especially in the endometrium. These cells also expressed CD8, CD2, and AsialoGM1. In the subepithelial stroma, the numbers were greatest during proestrus and estrus; in ovariectomized animals, they were severely decreased, but returned to normal with estrogen supplementation. At the time of blastocyst attachment (Day 6), NKR-P1+ cells were few around the implant and in the decidualizing stroma. However, on Day 8, substantial numbers were present in the mesometrial decidua only, and many of these cells expressed the cytolytic protein perforin. By Day 10, NKR-P1+ cells were common within the inner muscle at the base of the mesometrial triangle and in the developing metrial gland, often containing perforin. Larger numbers of perforin+ cells were present in the central decidua towards the ectoplacental cone, and many were weakly NKR-P1+ only. On Day 12, NKR-P1+ cells were almost completely restricted to the metrial gland, with few in decidua, and many were weakly positive. Substantially more perforin-containing cells were seen, indicating that many had lost detectable NKR-P1. This distribution pattern from Days 6-12 is similar to that described for GMG cells and demonstrates that in the rat they belong to the NK cell lineage. These cells were also CD8+ and AsialoGM1+ but negative for CD2 and class II histocompatibility antigens, which is very different from interleukin-2-activated NK cells which they resemble morphologically. The loss during differentiation of NKR-P1 and CD2, which are involved in target adhesion and triggering of NK cells, is consistent with the poor cytolytic capacity reported for these cells.