Abstract
Efficient IgA transcytosis is critical for the maintenance of a homeostatic microbiota. In the canonical model, locally-secreted dimeric (d)IgA reaches the polymeric immunoglobulin receptor (pIgR) on intestinal epithelium via simple diffusion. A role for integrin αE(CD103)β7 during transcytosis has not been described, nor its expression by intestinal B cell lineage cells. We found that αE-deficient (αE−/−) mice have a luminal IgA deficit, despite normal antibody-secreting cells (ASC) recruitment, local IgA production and increased pIgR expression. This deficit was not due to dendritic cell (DC)-derived retinoic acid (RA) nor class-switching defects, as stool from RAG−/− mice reconstituted with αE−/− B cells was also IgA deficient. Flow cytometric, ultrastructural and transcriptional profiling showed that αEβ7-expressing ASC represent an undescribed subset of terminally-differentiated intestinal plasma cells (PC) that establishes direct cell to cell contact with intestinal epithelium. We propose that IgA not only reaches pIgR through diffusion, but that αEβ7+ PC dock with E-cadherin-expressing intestinal epithelium to directly relay IgA for transcytosis into the intestinal lumen.
Highlights
Secretory Immunoglobulin A (SIgA) is critical for the control of the intestinal microbiota
CD103 is widely used as a surface marker for hairy cell leukemia, a B cell cancer.[6] αEβ7 is expressed by intraepithelial lymphocytes (IEL)[7] and mediates their interactions with intestinal epithelial cells (IEC) via E-cadherin.[8,9]
This finding is attributable to the absence of α4β7/MAdCAM-1mediated antibody-secreting cells (ASC) recruitment rather than to the αEβ7 defect, as this is observed in MAdCAM-1-deficient mice[1,3]
Summary
Secretory Immunoglobulin A (SIgA) is critical for the control of the intestinal microbiota. CD103 is widely used as a surface marker for hairy cell leukemia, a B cell cancer.[6] αEβ7 is expressed by intraepithelial lymphocytes (IEL)[7] and mediates their interactions with intestinal epithelial cells (IEC) via E-cadherin.[8,9] A mucosal dendritic cell (DC) subset expresses αEβ7.10 This DC subset was later found to be a major producer of retinoic acid (RA)[11], critical for induction of a guthoming phenotype, regulatory T cells (Treg) and IgA classswitching.[12,13,14] the physiologic role of the integrin in this DC subset remains unclear, as CD103−/− DC are not impaired on their ability to imprint a gut-homing phenotype to T cells.[15] αEβ7 has been reported in a subset of B cells at the nasal mucosa and the head and neck.[16,17] In the intestine, by contrast, neither its expression by cells of the B cell lineage nor its potential involvement in IgA luminal transport have been recognized.[18] Here, we report on an undescribed subset of terminallydifferentiated αEβ7-expressing IgA+ PC that establish direct contact with E-cadherin/pIgR-expressing IEC. We identify a new role for αEβ7 during IgA transcytosis and propose a novel mechanism of direct IgA relay to IEC by PC for its transcytosis into the intestinal lumen
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