Editors' ChoiceDevelopment

Adaptive regulation of mammary growth

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Sci. Signal.  29 Sep 2015:
Vol. 8, Issue 396, pp. ec277
DOI: 10.1126/scisignal.aad5159

Breast tissue contains immune cells, which are secreted in milk and can affect the progression of breast cancer. Innate immune cells regulate the postnatal development of the mouse mammary gland, and Plaks et al. demonstrate that adaptive immune cells do so as well. CD11c is a cell surface marker of dendritic cells and some macrophages, both of which can function as antigen-presenting cells (APCs) that activate T cells. CD11c+ cells with markers characteristic of APCs and CD4+ and CD8+ T cells were associated with the mammary epithelium during branching in pubertal mice. T helper 1 (TH1) cells were the most abundant type of CD4+ T cells in the mammary epithelium in vivo, and mammary gland branching was reduced in mice that had an overabundance of TH1 cells. Compared with controls, mammary tissue excised from mice lacking CD4+ and CD8+ T cells or depleted of CD11c+ cells exhibited increased epithelial ductal branching when cultured as organoids. Experiments with antibodies that specifically blocked APC-mediated activation of CD4+ T cells or of CD8+ T cells showed that CD4+ T cells were responsible for limiting ductal branching in cultured mammary organoids. Exposing organoids to interferon-γ (IFN-γ), which is secreted by TH1 cells, stimulated signaling in the luminal cells that line the ducts, inhibited branching, and reduced the expression of some, but not all, markers of mature luminal cells and their progenitors, suggesting that IFN-γ disrupts luminal cell differentiation. Addition of IFN-γ–neutralizing antibodies to organoid cultures stimulated branching, even if the cultured tissue had an overabundance of CD4+ TH1 cells. Thus, CD11c+ APCs locally stimulate the differentiation of CD4+ TH1 cells, which secrete IFN-γ, thereby limiting ductal outgrowth by suppressing the differentiation of luminal cells. The antigen presented by APCs to T cells in this context remains to be discovered. Travis and Streuli discuss the potential implications for these findings in the context of disease.

V. Plaks, B. Boldajipour, J. R. Linnemann, N. H. Nguyen, K. Kersten, Y. Wolf, A.-J. Casbon, N. Kong, R. J. E. van den Bijgaart, D. Sheppard, A. C. Melton, M. F. Krummel, Z. Werb, Adaptive immune regulation of mammary postnatal organogenesis. Dev. Cell 34, 493–504 (2015). [PubMed]

M. A. Travis, C. H. Streuli, The immunology of breast development. Dev. Cell 34, 487–488 (2015). [PubMed]