An integrin αEβ7-dependent mechanism of IgA transcytosis requires direct plasma cell contact with intestinal epithelium

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.

Krüppel-like factor 2 controls IgA plasma cell compartmentalization and IgA responses

“…Itgβ7 can pair with Itgα4 and ItgαE chains to form the heterodimeric Itgα4β7 and ItgαEβ7 surface receptors. Itgα4β7 is crucial for the recruitment of immune cells to the LP, whereas ItgαEβ7 is expressed on a subset of IgA + PC and establishes the contact with intestinal epithelial cells, thereby promoting transcytosis of IgA 55 , 56 . Thus, KLF2 controls Itgβ7-mediated recruitment of IgA + PC to the LP and might be involved in ItgαEβ7-mediated interaction of IgA + PC with the epithelium.…”

The intestine: A highly dynamic microenvironment for IgA plasma cells

“…In a recent study, Guzman and colleagues revealed that a subpopulation of IgA plasmablasts in the LP express integrin αEβ7 allowing them to interact physically with IECs via E-Cadherin ( Figure 2 ). This intimate plasma cell-IEC interaction allows the efficient transcytosis of dimeric IgA via the poly-IgR (p-IgR) on IECs to the gut lumen ( 83 ). Dimeric IgA consist of two IgA monomers that are covalently connected by the joining chain (J-chain) ( 84 , 85 ).…”

“…In another study, the analysis of liver cells from TCDD-treated mice showed that AhR can potentially induce the expression of E-Cadherin when interacting with KLF6 as a co-activator ( 170 ). As E-cadherin may be necessary for cell-cell interaction between IECs and lymphocytes in the intestine ( 83 ), this mechanism has to be considered when analyzing the role of AhR in the intestinal plasma cell niche. However, functional studies are still missing, and it must be determined whether AhR interacts with KLF6 to induce E-Cadherin in IECs.…”

“…They demonstrated that AhR-deficient intestinal CD4 + TCRβ + Foxp3 + Tregs lack the expression of CD103 and the chemokine CCL20, which is involved in cell migration. CD103 expression in Tregs is important for their activation and retention at the site of inflammation and CD103 can also be found on IgA plasma cells ( 83 ). Furthermore, mice treated with the AhR agonist FICZ expressed more CD103 in intestinal Tregs than control-treated animals, implying CD103 as a potential AhR target gene.…”

The Interplay between Integrins and Immune Cells as a Regulator in Cancer Immunology

“…The AKT signaling pathway ultimately mediates cell survival, thereby inhibiting apoptosis and increasing the production of plasma cells [ 93 , 94 ]. Likewise, toll-like receptor 9 (TLR9) also triggers the interaction of α4β1 integrins with VCAM-1, which promotes the retention and homing of circulating B cells in secondary lymphoid organs, and homing of the post-germinal central memory B cells into bone marrow or mucosal tissues to differentiate into plasma cells [ 95 ]. Research showed that IgA was secreted into the enteric cavity directly by the docking between αEβ7+ plasma cells and E-cadherin-expressing enterocytes, which identified αEβ7 integrins as an important target for the treatment of inflammatory bowel disease and provides new approaches for drug research and development, such as with natalizumab and vedolizumab.…”