Interleukin (IL)-21 promotes intestinal IgA response to microbiota

Area of Science:

• Immunology
• Microbiology
• Gastroenterology

Background:

• Intestinal T helper type 17 (Th17) and T follicular helper (Tfh) cells are vital for mucosal immunoglobulin A (IgA) production against commensal microbiota.
• The precise roles of Th17 and Tfh cytokines in regulating the mucosal IgA response remain incompletely understood.

Purpose of the Study:

• To elucidate the function of interleukin (IL)-17 and IL-21 signaling in regulating intestinal IgA production.
• To investigate the mechanisms by which IL-21 influences B-cell differentiation, IgA class switch recombination (CSR), and B-cell homing.

Main Methods:

• Analysis of IgA levels in mice deficient in IL-17 or IL-21 signaling.
• In vitro studies assessing the effects of IL-21 on B-cell differentiation and IgA production, including transforming growth factor β1 (TGFβ1) and retinoic acid (RA) involvement.
• T-cell reconstitution experiments in T-cell-deficient mice with antigen-specific Th17 cells and IL-21 neutralization.
• Assessment of B-cell homing markers, such as α4β7, under IL-21 influence.

Main Results:

• Intestinal IgA production was impaired in mice lacking IL-17 or IL-21 signaling.
• IL-21, but not IL-17, significantly augmented B-cell differentiation into IgA+ cells, mediated by TGFβ1, and accelerated IgA CSR.
• IL-21, in conjunction with RA, induced IgA+ B-cell development and production, driving autocrine TGFβ1 for IgA CSR.
• Restoring Th17 cells in T-cell-deficient mice increased intestinal IgA+ B cells and IgA production, an effect blocked by IL-21 neutralization.
• IL-21 promoted intestinal B-cell homing via α4β7 expression, potentiated by TGFβ and RA.

Conclusions:

• IL-21 plays a critical role in augmenting intestinal IgA production by enhancing IgA+ CSR, B-cell differentiation, and production.
• IL-21 contributes to robust intestinal IgA levels by promoting B-cell homing into the intestine.
• Microbiota-specific Th17 and Tfh cells, through IL-21 secretion, are key regulators of intestinal mucosal immunity.