An Indispensable Role for the Chemokine Receptor CCR10 in IgA Antibody-Secreting Cell Accumulation

Abstract

The differential expression of chemokines and chemokine receptors, by tissues and leukocytes, respectively, contributes to the specific accumulation of leukocyte subsets to different tissues. CCR10/CCL28 interactions are thought to contribute to the accumulation of IgA Ab-secreting cells (ASC) to mucosal surfaces, such as the gastrointestinal tract and the lactating mammary gland. Although the role of CCL28 in lymphocyte homing is well established, direct in vivo evidence for CCR10 involvement in this process has not been previously shown. In this study, we describe the generation of a CCR10-deficient mouse model. Using this model, we demonstrate that CCR10 is critical for efficient localization and accumulation of IgA ASC to the lactating mammary gland. Surprisingly, IgA ASC accumulation to the gastrointestinal tract is minimally impacted in CCR10-deficient mice. These results provide the first direct evidence of CCR10 involvement in lymphocyte homing and accumulation in vivo, and demonstrate that reliance on CCR10-mediated recruitment of IgA ASC varies dramatically within mucosal tissues.

Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines

“…Levels of total IgA antibodies in feces were similar in CCR10 EGFP/EGFP , CCR10 +/EGFP , and WT mice (Fig. 1B), consistent with the normal numbers of intestinal IgA + plasma cells and results of a recent report (16). The IgA + plasma cells of CCR10 EGFP/EGFP and control mice also had the similar capacity to produce IgA in vitro (Fig.…”

“…However, the anti-CCL28 antibody treatment did not have any effect on the IgA response to intestinal rotavirus infection (15). More directly, there was no defect of homeostatic IgA production in intestines of CCR10-KO mice (16). These studies suggest that CCR10/ligands are not critically required for normal levels of IgA responses to commensal bacteria or pathogen infection, and the functional importance of CCR10 in the intestinal IgA response is still unclear.…”

“…Because no other chemokine receptor could substitute for the CCR10-mediated migration of IgA + cells toward its mucosal ligand CCL28 in vitro (16), it is unclear why the CCR10 KO did not have much effect, particularly in the large intestine, where the ligand (CCL25) for another major gut-homing molecule, CCR9, is not expressed (9). We then tested whether CCR10-deficient IgA plasma cells were defective in migration into intestines by using an in vivo migration assay in which similar numbers of EGFP + IgA + cells of CCR10 +/EGFP and CCR10 EGFP/EGFP mice were cotransferred into WT mice.…”

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.…”

“…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). These findings suggest a broad and unifying role for the interaction of CCR10 and MEC/CCL28 in mucosal IgA induction.…”