Redundant Role of Chemokines CCL25/TECK and CCL28/MEC in IgA+ Plasmablast Recruitment to the Intestinal Lamina Propria After Rotavirus Infection

Abstract

Rotaviruses (RV) are the most important cause of severe childhood diarrheal disease. In suckling mice, infection with RV results in an increase in total and virus-specific IgA+ plasmablasts in the small intestinal lamina propria (LP) soon after infection, providing a unique opportunity to study the mechanism of IgA+ cell recruitment into the small intestine. In this study, we show that the increase in total and RV-specific IgA+ plasmablasts in the LP after RV infection can be blocked by the combined administration of Abs against chemokines CCL25 and CCL28, but not by the administration of either Ab alone. RV infection in CCR9 knockout mice still induced a significant accumulation of IgA+ plasmablasts in the LP, which was blocked by the addition of anti-CCL28 Ab, confirming the synergistic role of CCL25 and CCL28. The absence of IgA+ plasmablast accumulation in LP following combined anti-chemokine treatment was not due to changes in proliferation or apoptosis in these cells. We also found that coadministration of anti-CCL25 and anti-CCL28 Abs with the addition of anti-α4 Ab did not further inhibit IgA+ cell accumulation in the LP and that the CCL25 receptor, CCR9, was coexpressed with the intestinal homing receptor α4β7 on IgA+ plasmablasts. Finally, we showed that RV infection was associated with an increase in both CCL25 and CCL28 in the small intestine. Hence, our findings indicate that α4β7 along with either CCR9 or CCR10 are sufficient for mediating the intestinal migration of IgA+ plasmablasts during RV infection.

CC Chemokine Receptors and Chronic Inflammation—Therapeutic Opportunities and Pharmacological Challenges

“…Further detailed analysis of lymphocyte homing in wild-type and CCR9-deficient mice revealed CCR9 expression on IgA 1 plasma cells in mesenteric lymph nodes and Peyer's patches that was downregulated on migration to the small intestine (Pabst et al, 2004). Ccr9 2/2 animals failed to mount a normal IgA response to orally administered antigens (Pabst et al, 2004), although Ccr9 2/2 animals showed no gross defect in rotavirus-specific plasmablast recruitment to the intestine during rotavirus infection (Feng et al, 2006). Given the expression of the CCR9 receptor on guthoming lymphocytes in the blood and lymphocytes in the gut, a number of laboratories looked at the effects of CCR9 ablation and CCL25 blockade in mouse models of intestinal inflammation.…”

Delivery strategies to enhance oral vaccination against enteric infections

“…The integrin α4β7 allows lymphocytes to specifically attach to the mucosal addressin, cell adhesion molecule-1 (MADCAM-1) [74,80] expressed on endothelial cells of the post capillary venules in the gut lamina propria (LP) thus guiding lymphocytes toward these key gut effector sites [66]. The chemokine receptors CCR9 and CCR10 allow lymphocyte homing to the small or large intestine where endothelial cells produce CCL25 and CCL28 respectively, adding further gut homing specificity [81,82]. Effector responses can consequently be manifested in the LP or between epithelial cells in the case of intra-epithelial lymphocytes (IELs) [83][84][85].…”

Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab

“…As a result, antibodysecreting cells in the lamina propria express ␣ 4 ␤ 7 integrin. 3,29 Further, CCR10 expression by IgA ϩ plasmablasts mediates their migration toward CCL28, 20,30 which is expressed in gut-and airway-associated lymphoid tissues. 31 Consistently, CCR10 is abundantly expressed by IgA-secreting cells residing within human mucosal effector sites.…”