Parity-induced changes to mammary epithelial cells control NKT cell expansion and mammary oncogenesis

Cell Rep. 2021 Dec 7;37(10):110099. doi: 10.1016/j.celrep.2021.110099.


Pregnancy reprograms mammary epithelial cells (MECs) to control their responses to pregnancy hormone re-exposure and carcinoma progression. However, the influence of pregnancy on the mammary microenvironment is less clear. Here, we used single-cell RNA sequencing to profile the composition of epithelial and non-epithelial cells in mammary tissue from nulliparous and parous female mice. Our analysis indicates an expansion of γδ natural killer T-like immune cells (NKTs) following pregnancy and upregulation of immune signaling molecules in post-pregnancy MECs. We show that expansion of NKTs following pregnancy is due to elevated expression of the antigen-presenting molecule CD1d on MECs. Loss of CD1d expression on post-pregnancy MECs, or overall lack of activated NKTs, results in mammary oncogenesis. Collectively, our findings illustrate how pregnancy-induced changes modulate the communication between MECs and the immune microenvironment and establish a causal link between pregnancy, the immune microenvironment, and mammary oncogenesis.

Keywords: Brca1 KO; CD1d; NKT cells; mammary development; pregnancy.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD1d / metabolism
  • Cell Communication
  • Cell Proliferation*
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology*
  • Cell Transformation, Neoplastic / metabolism
  • Cell Transformation, Neoplastic / pathology
  • Epithelial Cells / immunology*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, BRCA1
  • Genes, myc
  • Lymphocyte Activation*
  • Mammary Glands, Animal / immunology*
  • Mammary Glands, Animal / metabolism
  • Mammary Glands, Animal / pathology
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / metabolism
  • Mammary Neoplasms, Experimental / pathology
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Natural Killer T-Cells / immunology*
  • Natural Killer T-Cells / metabolism
  • Parity*
  • Pregnancy
  • Receptors, Antigen, T-Cell, gamma-delta / metabolism
  • Signal Transduction
  • Tumor Microenvironment


  • Antigens, CD1d
  • CD1d antigen, mouse
  • Receptors, Antigen, T-Cell, gamma-delta