Uterine Natural Killer Cells Do Not Require Interleukin-2 for Their Differentiation or Maturation

Abstract

Natural Killer lymphocytes (NK cells) from the pregnant uterus and from other tissues in pregnant and nonpregnant mammals can be stimulated by interleukin-2 (IL-2) during culture to become Lymphokine Activated Killer (LAK) cells. The susceptibility of cultured trophoblast cells to lysis by LAK cells raises the enigma of why uterine (u) NK cells that are characterized by morphology and by surface phenotyping as "activated," and thus potentially damaging to the placenta, become localized to implantation sites during normal rodent gestation. uNK cells migrating from explant cultures of the metrial gland were assessed for expression (mRNA and protein) of each chain of the IL-2 receptor (IL-2R). Implantation sites from transgenic mice lacking a functional IL-2 gene were examined histologically for the differentiation of mature, granulated uNK cells. Early post-implantation, mRNA from migrating uNK cells contains transcripts for all three chains of the IL-2R. Only IL-2Rgamma was expressed at day 12 of gestation; expression of this gene was also lost by day 16. Loss of IL-2R transcription did not result in loss of protein expression; however, it did coincide with loss of uNK cell viability in vivo. Apparently normal differentiation of uNK cells occurred in IL-2(-/-) mice and in doubly mutant IL-2(-/-).beta2m(-/-) mice. Thus, despite uNK cell expression of the full IL-2R at day 8 of gestation, IL-2 is not required for the maturation of uNK cells to their fully granulated form or for normal placental development.