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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.

SUBMITTER: Guzman M

PROVIDER: S-EPMC8528714 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundConflicting results regarding changes in mucosal IgA production or in the proportions of IgA plasma cells in the small and large intestines during HIV-infection have been previously reported. Except in individuals repeatedly exposed to HIV-1 but yet remaining uninfected, HIV-specific IgAs are frequently absent in mucosal secretions from HIV-infected patients. However, little is known about the organization and functionality of mucosal B-cell follicles in acute HIV/SIV infection during which a T-dependent IgA response should have been initiated. In the present study, we evaluated changes in B-cell and T-cell subsets as well as the extent of apoptosis and class-specific plasma cells in Peyer's Patches, isolated lymphoid follicles, and lamina propria. Plasma levels of IgA, BAFF and APRIL were also determined.ResultsPlasma IgA level was reduced by 46% by 28 days post infection (dpi), and no IgA plasma cells were found within germinal centers of Peyer's Patches and isolated lymphoid follicles. This lack of a T-dependent IgA response occurs although germinal centers remained functional with no sign of follicular damage, while a prolonged survival of follicular CD4+ T-cells and normal generation of IgG plasma cells is observed. Whereas the average plasma BAFF level was increased by 4.5-fold and total plasma cells were 1.7 to 1.9-fold more numerous in the lamina propria, the relative proportion of IgA plasma cells in this effector site was reduced by 19% (duodemun) to 35% (ileum) at 28 dpi.ConclusionOur data provide evidence that SIV is unable to initiate a T-dependent IgA response during the acute phase of infection and favors the production of IgG (ileum) or IgM (duodenum) plasma cells at the expense of IgA plasma cells. Therefore, an early and generalized default in IgA production takes place during the acute of phase of HIV/SIV infection, which might impair not only the virus-specific antibody response but also IgA responses to other pathogens and vaccines as well. Understanding the mechanisms that impair IgA production during acute HIV/SIV infection is crucial to improve virus-specific response in mucosa and control microbial translocation.

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

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