Got Milk? Investigating the role of mammary intraepithelial lymphocytes in promoting lactogenesis 2446

Abstract Description Pregnancy and lactation bring about dynamic changes to the mammary gland tissue, including exposure to the outside environment, yet the role of lymphocytes in promoting this rapid tissue remodeling remain poorly understood. We present a comprehensive analysis of the transcriptional and protein expression profiles of mammary lymphocytes at different stages of parity. Pregnancy and lactation led to the expansion of several subsets of T cells, most notably a striking increase in CD8αα+ TCRαβ+ T cells, resembling intraepithelial lymphocytes (IELs) that are typically found in mucosal tissues. Confocal imaging confirmed that these T cells were intraepithelial, with their numbers increasing alongside epithelial cell proliferation during pregnancy and lactation. TCR sequencing revealed shared clonotypes between mammary and intestinal IELs, suggesting that mammary IELs may migrate from the gut along the entero-mammary axis, challenging the traditional view that IELs are tissue-resident. We also identified IEL-like cells in human milk, indicating conserved immune functions across species. Mammary T cell expansion was partially dependent on microbes, as germ-free mice displayed a reduction in mammary T cells and IEL numbers, with transcriptional changes showing decreased cytotoxic gene expression. Our results improve our understanding of lactation immunology and provide evidence for how rapid mucosal host-defense responses can be established in non-mucosal tissues. Funding Sources This work was supported by NIH grants RO1-AI150686 to CB, R24-072073 to the ImmGen Consortium, NIH-NCI CCSG: P30 CA01495, and Shared Instrumentation Grants S10-OD023689 to the Salk Institute core facilities (FCCF, NGS). Topic Categories Mucosal and Regional Immunology (MUC)