Critical roles of chemokine receptor CCR10 in regulating memory IgA responses in intestines

Abstract

Chemokine receptor CCR10 is expressed by all intestinal IgA-producing plasma cells and is suggested to play an important role in positioning these cells in the lamina propria for proper IgA production to maintain intestinal homeostasis and protect against infection. However, interfering with CCR10 or its ligand did not impair intestinal IgA production under homeostatic conditions or during infection, and the in vivo function of CCR10 in the intestinal IgA response remains unknown. We found that an enhanced generation of IgA + cells in isolated lymphoid follicles of intestines offset defective intestinal migration of IgA + cells in CCR10-KO mice, resulting in the apparently normal IgA production under homeostatic conditions and in primary response to pathogen infection. However, the compensatorily generated IgA + cells in CCR10-KO mice carried fewer hypermutations in their Ig heavy chain alleles than those of WT mice, indicating that their IgA repertoires are qualitatively different, which might impact the intestinal homeostasis of microflora. In addition, CCR10-deficient long-lived IgA-producing plasma cells and IgA + memory B cells generated against the pathogen infection could not be maintained properly in intestines. Consequently, IgA memory responses to the pathogen reinfection were severely impaired in CCR10-KO mice. These findings elucidate critical roles of CCR10 in regulating the intestinal IgA response and memory maintenance and could help in design of vaccines against intestinal and possibly other mucosal pathogens.

Generation of colonic IgA-secreting cells in the caecal patch

“…In addition, ILFs have been shown to increase in number in the small and large intestines of mice lacking CCR10, which show normal numbers of IgA-secreting cells in the intestine 17 . Enlarged ILFs are considered to serve to compensate for the defective recruitment of Ccr10 À / À IgAsecreting cells to the intestine.…”

“…CCR9 is responsible for the homing to the small intestine 16 , whereas CCR10 contributes to the migration to both the small and large intestines 17,34,35 . IgA þ cells in the caecal patch expressed higher levels of CCR9 and CCR10 than the cells in Peyer's patches.…”

“…ILFs are sites of generation of IgA-secreting cells with differential mechanisms to those from Peyer's patches 26 . In the absence of CCR10, SILTs including ILFs have been reported to enlarge and increase in number, which contributed to the maintenance of a normal number of IgA-secreting cells in the intestine of Ccr10 À / À mice 17 . Therefore, we measured the number of SILTs in the large intestine of appendectomized mice by whole-mount staining of B220 þ cells at 8 weeks after conventionalization (Fig.…”

“…It has recently been reported that IgAs derived from the small and large intestines have differential repertoires 15 . It has also been reported that CCR9 mediates migration of IgA-secreting cells to the small intestine but not the large intestine 16 , whereas CCR10 is involved in migration to both the small and large intestines 17 . However, it remains unclear where IgA-secreting plasma cells that migrate to the large intestine are generated.…”

Immunological Status of Isolated Lymphoid Follicles After Intestinal Transplantation

“…These small lymphoid structures seated all over the small bowel are highly dynamic serving as an important inductive site for IgA synthesis confronting changes in the microbiota (15,16). ILF hyperplasia and uncontrolled growth of commensals were shown in an activation-induced cytidine deaminase (AICDA) null mice, where class switch recombination and somatic hypermutation (SHM) are inhibited (17), whereas reduced number of ILFs were detected in antibiotic-treated or in germ-free mice (18,19). Little is known about human ILFs in general and to our knowledge, no studies of ILFs from the intestinal allograft have been reported.…”