Assessment of requirements for IL-15 and IFN regulatory factors in uterine NK cell differentiation and function during pregnancy.
In mouse and human, precursors of NK cell lineage home to decidualizing uteri. To assess the requirement for IL-15, an essential cytokine for NK differentiation in lymphoid tissue, on uterine NK (uNK) cell differentiation, implantation sites from IL-15(-/-) mice were analyzed histologically. IL-15(-/-) implantation sites had no uNK cells, no spiral-artery modification, and lacked the decidual integrity found in normal mice. IL-15(-/-) recipients of C57BL/6 marrow displayed similar pathology. However, implantation sites from recombination-activating gene-2(-/-)gamma(c)(-/-) (alymphoid) recipients of IL-15(-/-) marrow showed normal uNK cells, modified spiral arteries, and well-developed decidua basalis. Deletion of the IFN-regulatory factor (IRF)-1, but not IRF-2 (factors important in peripheral NK cell differentiation) limited but did not prevent uNK cell development. In situ hybridization localized IRF-1 largely to placental trophoblast cells. IRF-1(-/-) marrow transplanted into recombination-activating gene-2(-/-)gamma(c)(-/-) displayed competence for full uNK cell differentiation. IL-15 mRNA expression at implantation sites of IRF-1(-/-) and C57BL/6 was similar, suggesting that, unlike in bone marrow and spleen, IRF-1 does not regulate IL-15 in the pregnant uterus. Terminal differentiation of uNK cells was not promoted in pregnant IRF-1(-/-) mice by 5-day infusion of murine rIL-15, suggesting that IRF-1 deficiency rather than IL-15 deficiency limits uNK cell differentiation in these mice. Further, IRF-1 regulates placental growth, birth weight, and postnatal growth of offspring. These studies indicate that uNK cell development and maturation share some aspects with NK cell development in other tissues, but also display distinctive tissue-specific regulation.
Ashkar
Ali A
AA
Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada. ashkara@mcmaster.ca
Black
Gordon P
GP
Wei
Qingxia
Q
He
Hong
H
Liang
Luchuan
L
Head
Judith R
JR
Croy
B Anne
BA
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010064:Embryo Implantation / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D005260:Female; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D007371:Interferon-gamma / Q000502:physiology*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage; D012097:Repressor Proteins; D013234:Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors; D014599:Uterus / Q000166:cytology* / Q000276:immunology / Q000378:metabolism
D004268:DNA-Binding Proteins; D050856:Interferon Regulatory Factor-1; D050836:Interferon Regulatory Factor-2; D019409:Interleukin-15; C494258:Irf1 protein, mouse; C494230:Irf2 protein, mouse; D010750:Phosphoproteins; D011257:Pregnancy Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D007371:Interferon-gamma