CCL28 Controls Immunoglobulin (Ig)A Plasma Cell Accumulation in the Lactating Mammary Gland and IgA Antibody Transfer to the Neonate

Abstract

The accumulation of immunoglobulin (Ig)A antibody-secreting cells (ASCs) in the lactating mammary gland leads to secretion of antibodies into milk and their passive transfer to the suckling newborn. This transfer of IgA from mother to infant provides transient immune protection against a variety of gastrointestinal pathogens. Here we show that the mucosal epithelial chemokine CCL28 is up-regulated in the mammary gland during lactation and that IgA ASCs from this tissue express CCR10 and migrate to CCL28. In vivo treatment with anti-CCL28 antibody blocks IgA ASC accumulation in the mammary gland, inhibiting IgA antibody secretion into milk and the subsequent appearance of antibody in the gastrointestinal tract of nursing neonates. We propose that CCL28 is a key regulator of IgA ASC accumulation in the mammary gland and thus controls the passive transfer of IgA antibodies from mother to infant.

Mucosa-Associated Epithelial Chemokine/CCL28 Expression in the Uterus Attracts CCR10+ IgA Plasma Cells following Mucosal Vaccination via Estrogen Control

“…4). It was suggested previously that CCR10 is expressed selectively by IgA ASCs, including circulating IgA + plasmablasts, and by most IgA + plasma cells in the salivary glands, small and large intestines, appendix, and tonsils (14)(15)(16)32). Our results suggest that CCR10 + IgA ASCs in the uterus might migrate from cervical LNs but not from iliac LNs that directly drain LNs of reproductive tissues.…”

“…The uterine epithelium is a type I mucosa that is covered by simple single-cell epithelia, whereas the lower genital tract including the vaginal canal is type II mucosa covered by stratified squamous epithelia, which share many features with the skin (36,37). MEC/CCL28 is expressed in type I mucosa, including the large intestinal epithelial cells and lactating mammary gland (14,15). Of note, total and Ag-specific IgA plasma cells isolated from lactating mammary glands were attracted specifically toward the MEC/CCL28 after i.n.…”

“…Mucosaassociated epithelial chemokine (MEC/CCL28), a well-known ligand for CCR10, is commonly produced by epithelial cells at several mucosal sites and attracts IgA-but not IgG-or IgMproducing ASCs into the intestines, lungs, and oral cavity (14). In addition, a previous study revealed that MEC/CCL28 attracts IgA ASC migration to the lactating mammary gland and supports IgA Ab transfer to the neonate (15). In CCR10 2/2 mice, accumulation of IgA ASCs in the gastrointestinal tract is minimally affected, whereas IgA ASCs in the lactating mammary gland are entirely absent, indicating that reliance on CCR10-mediated recruitment of IgA ASCs varies within mucosal tissues (16).…”

“…Previous studies found that chemokines and tissue-specific adhesion molecules are involved in the migration of Ab-secreting cells (ASCs) (13). Of these, CCR9 and CCR10 enable plasma B cells to migrate into mucosal tissues (14,15). Mucosaassociated epithelial chemokine (MEC/CCL28), a well-known ligand for CCR10, is commonly produced by epithelial cells at several mucosal sites and attracts IgA-but not IgG-or IgMproducing ASCs into the intestines, lungs, and oral cavity (14).…”

Lessons from mother: Long-term impact of antibodies in breast milk on the gut microbiota and intestinal immune system of breastfed offspring

“…The mucosal epithelial chemokine CCL28 is up-regulated in the mammary gland during lactation, and plays a key role in attracting IgA C CCR10 C antibody-secreting cells that were primed in mucosal lymphoid tissues of the intestinal and Keywords: breastfeeding, gut microbiota, gene expression, intestinal epithelial cells, inflammatory bowel disease, polymeric immunoglobulin receptor, secretory IgA respiratory tracts. 13 Thus, a significant proportion of the SIgA antibodies in breast milk are targeted against microbes in the mother's gastrointestinal tract, which are the same microbes that will seed the gut microbiota of the infant (for a review see ref. 14).…”