Intrarectal Immunization and IgA Antibody-Secreting Cell Homing to the Small Intestine

Abstract

According to the current paradigm, lymphocyte homing to the small intestine requires the expression of two tissue-specific homing receptors, the integrin α4β7 and the CCL25 receptor CCR9. In this study, we investigated the organ distribution and the homing molecule expression of IgA Ab-secreting cells (ASCs) induced by intrarectal immunization with a particulate Ag, in comparison with other mucosal immunization routes. Intrarectal immunization induces gut-homing IgA ASCs that localize not only in the colon but also in the small intestine, although they are not responsive to CCL25, unlike IgA ASCs induced by oral immunization. The mucosal epithelial chemokine CCL28, known to attract all IgA ASCs, does not compensate for the lack of CCL25 responsiveness, because the number of Ag-specific cells is not decreased in the gut of CCR10-deficient mice immunized by the intrarectal route. However, Ag-specific IgA ASCs induced by intrarectal immunization express the integrin α4β7, and their number is considerably decreased in the gut of β7-deficient mice immunized by the intrarectal route, indicating that α4β7 enables these cells to migrate into the small intestine, even without CCL25 responsiveness. In contrast, IgA ASCs induced by intranasal immunization express low α4β7 levels and are usually excluded from the gut. Paradoxically, after intranasal immunization, Ag-specific IgA ASCs are significantly increased in the small intestine of β7-deficient mice, demonstrating that lymphocyte homing is a competitive process and that integrin α4β7 determines not only the intestinal tropism of IgA ASCs elicited in GALTs but also the intestinal exclusion of lymphocytes primed in other inductive sites.

Re-thinking the functions of IgA+plasma cells

“…For example, immunization by the intra-rectal route can induce a higher number of Ag-specific IgA C PC in the gut than the intra-nasal immunization route. 59 Once in the LP, these PC have access to survival factors that include APRIL and BAFF secreted by DC 60,61 as well as the production of APRIL from the intestinal epithelium itself 62 . Very recently it was shown that similar to what was observed in the BM, gut eosinophils, can secrete cytokines that promote IgA CSR and IgA C PC survival (APRIL, IL-6), thereby supporting an IgA C PC niche in the gut.…”

The Mucosal B Cell System

“…(See color plate section.) oxidative conversion of retinoids such as dietary vitamin A (Hammerschmidt et al, 2011), and high expression of α4β7 seems to be most decisive (Agnello et al, 2013). In the large intestine α4β7 appears to be assisted in the homing by the mucosa-associated epithelial chemokine MEC/ CCL28 as an additional cue for attracting circulating IgA + plasmablasts that coexpress high levels of CCR10 , as documented in humans after administration of oral Salmonella vaccinecontrasting the results obtained after parenteral vaccination (Sundström et al, 2008).…”

More robust gut immune responses induced by combining intranasal and sublingual routes for prime-boost immunization

“…21 , 30 In contrast, IgA-secreting cells primed at other mucosal inductive sites, such as those elicited by IN immunization in the LNs associated with airways, cannot efficiently occupy plasma cell niches in intestinal sites. 31 In addition, α4β7 +  plasma and memory B cells can be found after infection or experimental challenge with enteric pathogens as well as oral immunization. 32 These differential localization/homing of effector immune cells should be responsible for different immune response patterns in various organs and tissues.…”