Journal of Mammary Gland Biology and Neoplasia

, Volume 15, Issue 3, pp 329–339 | Cite as

Immune Cell Location and Function During Post-Natal Mammary Gland Development

  • Johanna R. Reed
  • Kathryn L. Schwertfeger


Post-natal mammary gland development requires complex interactions between the epithelial cells and various cell types within the stroma. Recent studies have illustrated the importance of immune cells and their mediators during the various stages of mammary gland development. However, the mechanisms by which these immune cells functionally contribute to mammary gland development are only beginning to be understood. This review provides an overview of the localization of immune cells within the mammary gland during the various stages of post-natal mammary gland development. Furthermore, recent studies are summarized that illustrate the mechanisms by which these cells are recruited to the mammary gland and their functional roles in mammary gland development.


Mammary gland Immune cell Immune mediator Macrophage Mast cell Eosinophil 



Transforming growth factor β


Tumor necrosis factor α




Polymorphonuclear leukocytes


Transforming growth factor α


Epidermal growth factor


T helper cell 1


T helper cell 2




Terminal end bud


Conjugated linoleic acid


Colony-stimulating factor 1


Mouse mammary tumor virus




Nerve growth factor


Colony stimulating factor 1 receptor


Immunoglobulin A


Vascular cell adhesion molecule-1



The authors would like to thank Dr. Jodi Goldberg for critical reading of this manuscript. JRR is supported by a pre-doctoral fellowship on the T32 CA009138 Cancer Biology Training Grant.


  1. 1.
    Watson CJ, Khaled WT. Mammary development in the embryo and adult: a journey of morphogenesis and commitment. Development. 2008;135(6):995–1003.CrossRefPubMedGoogle Scholar
  2. 2.
    Regan MC, Kirk SJ, Wasserkrug HL, Barbul A. The wound environment as a regulator of fibroblast phenotype. J Surg Res. 1991;50(5):442–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Adamson R. Role of macrophages in normal wound healing: an overview. J Wound Care. 2009;18(8):349–51.PubMedGoogle Scholar
  4. 4.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16(5):585–601.CrossRefPubMedGoogle Scholar
  5. 5.
    Glaros T, Larsen M, Li L. Macrophages and fibroblasts during inflammation, tissue damage and organ injury. Front Biosci. 2009;14:3988–93.CrossRefPubMedGoogle Scholar
  6. 6.
    Park JE, Barbul A. Understanding the role of immune regulation in wound healing. Am J Surg. 2004;187(5A):11S–6S.CrossRefPubMedGoogle Scholar
  7. 7.
    Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 2004;25(12):677–86.CrossRefPubMedGoogle Scholar
  8. 8.
    Mantovani A, Allavena P, Sica A. Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression. Eur J Cancer. 2004;40(11):1660–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61.CrossRefPubMedGoogle Scholar
  10. 10.
    Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Stone KD, Prussin C, Metcalfe DD. IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S73–80.PubMedGoogle Scholar
  12. 12.
    Abraham SN, St John AL. Mast cell-orchestrated immunity to pathogens. Nat Rev Immunol. 2010;10(6):440–52.CrossRefPubMedGoogle Scholar
  13. 13.
    Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z, et al. Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest. 2001;108(8):1151–8.PubMedGoogle Scholar
  14. 14.
    Rothenberg ME, Hogan SP. The eosinophil. Annu Rev Immunol. 2006;24:147–74.CrossRefPubMedGoogle Scholar
  15. 15.
    Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from discovery to therapy. Int Immunol. 2009;21(12):1303–9.CrossRefPubMedGoogle Scholar
  16. 16.
    Collins PD, Marleau S, Griffiths-Johnson DA, Jose PJ, Williams TJ. Cooperation between interleukin-5 and the chemokine eotaxin to induce eosinophil accumulation in vivo. J Exp Med. 1995;182(4):1169–74.CrossRefPubMedGoogle Scholar
  17. 17.
    Mould AW, Matthaei KI, Young IG, Foster PS. Relationship between interleukin-5 and eotaxin in regulating blood and tissue eosinophilia in mice. J Clin Invest. 1997;99(5):1064–71.CrossRefPubMedGoogle Scholar
  18. 18.
    Rothenberg ME. Eotaxin. An essential mediator of eosinophil trafficking into mucosal tissues. Am J Respir Cell Mol Biol. 1999;21(3):291–5.PubMedGoogle Scholar
  19. 19.
    Sanderson CJ. Interleukin-5, eosinophils, and disease. Blood. 1992;79(12):3101–9.PubMedGoogle Scholar
  20. 20.
    Sferruzzi-Perri AN, Robertson SA, Dent LA. Interleukin-5 transgene expression and eosinophilia are associated with retarded mammary gland development in mice. Biol Reprod. 2003;69(1):224–33.CrossRefPubMedGoogle Scholar
  21. 21.
    Ohno I, Lea RG, Flanders KC, Clark DA, Banwatt D, Dolovich J, et al. Eosinophils in chronically inflamed human upper airway tissues express transforming growth factor beta 1 gene (TGF beta 1). J Clin Invest. 1992;89(5):1662–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Todd R, Donoff BR, Chiang T, Chou MY, Elovic A, Gallagher GT, et al. The eosinophil as a cellular source of transforming growth factor alpha in healing cutaneous wounds. Am J Pathol. 1991;138(6):1307–13.PubMedGoogle Scholar
  23. 23.
    Teller P, White TK. The physiology of wound healing: injury through maturation. Surg Clin North Am. 2009;89(3):599–610.CrossRefPubMedGoogle Scholar
  24. 24.
    Gouon-Evans V, Rothenberg ME, Pollard JW. Postnatal mammary gland development requires macrophages and eosinophils. Development. 2000;127(11):2269–82.PubMedGoogle Scholar
  25. 25.
    Lilla JN, Werb Z. Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis. Dev Biol. 2010;337(1):124–33.CrossRefPubMedGoogle Scholar
  26. 26.
    Pollard JW, Hennighausen L. Colony stimulating factor 1 is required for mammary gland development during pregnancy. Proc Natl Acad Sci U S A. 1994;91(20):9312–6.CrossRefPubMedGoogle Scholar
  27. 27.
    Bourges D, Meurens F, Berri M, Chevaleyre C, Zanello G, Levast B, et al. New insights into the dual recruitment of IgA + B cells in the developing mammary gland. Mol Immunol. 2008;45(12):3354–62.CrossRefPubMedGoogle Scholar
  28. 28.
    Weisz-Carrington P, Roux ME, Lamm ME. Plasma cells and epithelial immunoglobulins in the mouse mammary gland during pregnancy and lactation. J Immunol. 1977;119(4):1306–7.PubMedGoogle Scholar
  29. 29.
    O’Brien J, Lyons T, Monks J, Lucia MS, Wilson RS, Hines L, et al. Alternatively activated macrophages and collagen remodeling characterize the postpartum involuting mammary gland across species. Am J Pathol. 2010;176(3):1241–55.CrossRefPubMedGoogle Scholar
  30. 30.
    O’Brien J, Schedin P. Macrophages in breast cancer: do involution macrophages account for the poor prognosis of pregnancy-associated breast cancer? J Mammary Gland Biol Neoplasia. 2009;14(2):145–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Harkonen PL, Vaananen HK. Monocyte-macrophage system as a target for estrogen and selective estrogen receptor modulators. Ann N Y Acad Sci. 2006;1089:218–27.CrossRefPubMedGoogle Scholar
  32. 32.
    Routley CE, Ashcroft GS. Effect of estrogen and progesterone on macrophage activation during wound healing. Wound Repair Regen. 2009;17(1):42–50.CrossRefPubMedGoogle Scholar
  33. 33.
    De M, Wood GW. Influence of oestrogen and progesterone on macrophage distribution in the mouse uterus. J Endocrinol. 1990;126(3):417–24.CrossRefPubMedGoogle Scholar
  34. 34.
    Russell JS, McGee SO, Ip MM, Kuhlmann D, Masso-Welch PA. Conjugated linoleic acid induces mast cell recruitment during mouse mammary gland stromal remodeling. J Nutr. 2007;137(5):1200–7.PubMedGoogle Scholar
  35. 35.
    Masso-Welch PA, Zangani D, Ip C, Vaughan MM, Shoemaker S, Ramirez RA, et al. Inhibition of angiogenesis by the cancer chemopreventive agent conjugated linoleic acid. Cancer Res. 2002;62(15):4383–9.PubMedGoogle Scholar
  36. 36.
    Gouon-Evans V, Lin EY, Pollard JW. Requirement of macrophages and eosinophils and their cytokines/chemokines for mammary gland development. Breast Cancer Res. 2002;4(4):155–64.CrossRefPubMedGoogle Scholar
  37. 37.
    Pixley FJ, Stanley ER. CSF-1 regulation of the wandering macrophage: complexity in action. Trends Cell Biol. 2004;14(11):628–38.CrossRefPubMedGoogle Scholar
  38. 38.
    Lin EY, Gouon-Evans V, Nguyen AV, Pollard JW. The macrophage growth factor CSF-1 in mammary gland development and tumor progression. J Mammary Gland Biol Neoplasia. 2002;7(2):147–62.CrossRefPubMedGoogle Scholar
  39. 39.
    Ingman WV, Wyckoff J, Gouon-Evans V, Condeelis J, Pollard JW. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev Dyn. 2006;235(12):3222–9.CrossRefPubMedGoogle Scholar
  40. 40.
    Gyorki DE, Asselin-Labat ML, van Rooijen N, Lindeman GJ, Visvader JE. Resident macrophages influence stem cell activity in the mammary gland. Breast Cancer Res. 2009;11(4):R62.CrossRefPubMedGoogle Scholar
  41. 41.
    Rothenberg ME, MacLean JA, Pearlman E, Luster AD, Leder P. Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia. J Exp Med. 1997;185(4):785–90.CrossRefPubMedGoogle Scholar
  42. 42.
    Colbert DC, McGarry MP, O'Neill K, Lee NA, Lee JJ. Decreased size and survival of weanling mice in litters of IL-5-/ -mice are a consequence of the IL-5 deficiency in nursing dams. Contemp Top Lab Anim Sci. 2005;44(3):53–5.PubMedGoogle Scholar
  43. 43.
    Dent LA, Strath M, Mellor AL, Sanderson CJ. Eosinophilia in transgenic mice expressing interleukin 5. J Exp Med. 1990;172(5):1425–31.CrossRefPubMedGoogle Scholar
  44. 44.
    Daniel CW, Robinson S, Silberstein GB. The transforming growth factors beta in development and functional differentiation of the mouse mammary gland. Adv Exp Med Biol. 2001;501:61–70.PubMedGoogle Scholar
  45. 45.
    Wilson E, Butcher EC. CCL28 controls immunoglobulin (Ig)A plasma cell accumulation in the lactating mammary gland and IgA antibody transfer to the neonate. J Exp Med. 2004;200(6):805–9.CrossRefPubMedGoogle Scholar
  46. 46.
    Watson CJ. Immune cell regulators in mouse mammary development and involution. J Anim Sci. 2009;87(13 Suppl):35–42.PubMedGoogle Scholar
  47. 47.
    Khaled WT, Read EK, Nicholson SE, Baxter FO, Brennan AJ, Came PJ, et al. The IL-4/IL-13/Stat6 signalling pathway promotes luminal mammary epithelial cell development. Development. 2007;134(15):2739–50.CrossRefPubMedGoogle Scholar
  48. 48.
    Baratta M, Motta M, Accornero P. Leptin reduces the inhibitory effect of IL-1 beta on beta-casein gene expression in differentiated mammary cells. Vet Res Commun. 2005;29 Suppl 2:153–5.CrossRefPubMedGoogle Scholar
  49. 49.
    Clarkson RW, Wayland MT, Lee J, Freeman T, Watson CJ. Gene expression profiling of mammary gland development reveals putative roles for death receptors and immune mediators in post-lactational regression. Breast Cancer Res. 2004;6(2):R92–109.CrossRefPubMedGoogle Scholar
  50. 50.
    Kaplan MH, Schindler U, Smiley ST, Grusby MJ. Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996;4(3):313–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Macpherson AJ, McCoy KD, Johansen FE, Brandtzaeg P. The immune geography of IgA induction and function. Mucosal Immunol. 2008;1(1):11–22.CrossRefPubMedGoogle Scholar
  52. 52.
    Low EN, Zagieboylo L, Martino B, Wilson E. IgA ASC accumulation to the lactating mammary gland is dependent on VCAM-1 and alpha4 integrins. Mol Immunol. 2010;47(7–8):1608–12.CrossRefPubMedGoogle Scholar
  53. 53.
    Strange R, Li F, Saurer S, Burkhardt A, Friis RR. Apoptotic cell death and tissue remodelling during mouse mammary gland involution. Development. 1992;115(1):49–58.PubMedGoogle Scholar
  54. 54.
    Stein T, Morris JS, Davies CR, Weber-Hall SJ, Duffy MA, Heath VJ, et al. Involution of the mouse mammary gland is associated with an immune cascade and an acute-phase response, involving LBP, CD14 and STAT3. Breast Cancer Res. 2004;6(2):R75–91.CrossRefPubMedGoogle Scholar
  55. 55.
    Lilla JN, Joshi RV, Craik CS, Werb Z. Active plasma kallikrein localizes to mast cells and regulates epithelial cell apoptosis, adipocyte differentiation, and stromal remodeling during mammary gland involution. J Biol Chem. 2009;284(20):13792–803.CrossRefPubMedGoogle Scholar
  56. 56.
    Lund LR, Bjorn SF, Sternlicht MD, Nielsen BS, Solberg H, Usher PA, et al. Lactational competence and involution of the mouse mammary gland require plasminogen. Development. 2000;127(20):4481–92.PubMedGoogle Scholar
  57. 57.
    Monks J, Smith-Steinhart C, Kruk ER, Fadok VA, Henson PM. Epithelial cells remove apoptotic epithelial cells during post-lactation involution of the mouse mammary gland. Biol Reprod. 2008;78(4):586–94.CrossRefPubMedGoogle Scholar
  58. 58.
    Weathington NM, van Houwelingen AH, Noerager BD, Jackson PL, Kraneveld AD, Galin FS, et al. A novel peptide CXCR ligand derived from extracellular matrix degradation during airway inflammation. Nat Med. 2006;12(3):317–23.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Department of Lab Medicine and Pathology, Graduate Program in Microbiology, Immunology and Cancer Biology, Masonic Cancer CenterUniversity of MinnesotaMinneapolisUSA

Personalised recommendations