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Critical Roles of Chemokine Receptor CCR10 in Regulating Memory Iga

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Critical Roles of Chemokine Receptor CCR10 in Regulating Memory Iga Critical roles of chemokine receptor CCR10 in PNAS PLUS regulating memory IgA responses in intestines Shaomin Hu, KangKang Yang, Jie Yang, Ming Li, and Na Xiong1 Center for Molecular Immunology and Infectious Diseases and Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA 16802 Edited by Rino Rappuoli, Novartis Vaccines, Siena, Italy, and approved September 12, 2011 (received for review January 5, 2011) Chemokine receptor CCR10 is expressed by all intestinal IgA-pro- specificIgA+ plasma cells could be maintained in the intestine for ducing plasma cells and is suggested to play an important role in a long time in the absence of antigenic stimulation (half-life > 16 positioning these cells in the lamina propria for proper IgA pro- wk), suggesting that unique intrinsic properties of the IgA- duction to maintain intestinal homeostasis and protect against producing plasma cells and intestinal environments might collabo- infection. However, interfering with CCR10 or its ligand did not rate to maintain the prolonged IgA production. However, mainte- impair intestinal IgA production under homeostatic conditions or nance of the antigen-specific IgA-producing plasma cells is during infection, and the in vivo function of CCR10 in the intestinal significantly affected by continuous presence of commensal bacte- IgA response remains unknown. We found that an enhanced ria, which induce generation of new IgA-producing plasma cells generation of IgA+ cells in isolated lymphoid follicles of intestines that replace the existing antigen-specificIgA+ cells in the intestine. offset defective intestinal migration of IgA+ cells in CCR10-KO mice, Molecular factors involved in the long-term IgA maintenance are resulting in the apparently normal IgA production under homeo- largely unknown and it is also not well understood how IgA memory static conditions and in primary response to pathogen infection. responses to pathogen infection are regulated in the intestines. However, the compensatorily generated IgA+ cells in CCR10-KO mice Chemokine receptor CCR10 is expressed on nearly all IgA+ carried fewer hypermutations in their Ig heavy chain alleles than plasma cells and is suggested to play an important role in those of WT mice, indicating that their IgA repertoires are qualita- directing migration of the IgA+ cells generated in Peyer patches tively different, which might impact the intestinal homeostasis of or other mucosa-associated lymphoid tissues into effector sites microflora. In addition, CCR10-deficient long-lived IgA-producing such as the intestinal LP through interaction with its mucosa- + plasma cells and IgA memory B cells generated against the patho- specific ligand CCL28 expressed by intestinal epithelial cells (9– gen infection could not be maintained properly in intestines. Con- 12). Consistent with this notion, intestinal, but not systemic, sequently, IgA memory responses to the pathogen reinfection were immunization of humans efficiently generated CCR10+ antigen- severely impaired in CCR10-KO mice. These findings elucidate critical specific IgA+ cells (13). In addition, most human bloodborne roles of CCR10 in regulating the intestinal IgA response and memory IgA+ plasma cells express CCR10, suggesting that they originate maintenance and could help in design of vaccines against intestinal from mucosal responses (14). and possibly other mucosal pathogens. Despite the multiple lines of evidence implicating CCR10 in the intestinal IgA response, the role of CCR10 in this process is not CCL28 | citrobacter | gut-homing | T cell-dependent response | clear. One earlier study reported that neutralizing the CCR10 li- T cell-independent response gand CCL28 with antibodies impaired intestinal IgA production in response to oral immunization of cholera toxin (CT) in a mouse gA antibodies are important components of the mucosal im- model (9). However, the anti-CCL28 antibody treatment did not Imune system. In the intestine, they are produced by IgA- have any effect on the IgA response to intestinal rotavirus in- producing plasma cells predominantly localized in the lamina fection (15). More directly, there was no defect of homeostatic IgA propria (LP) and secreted into the lumen, where they play im- production in intestines of CCR10-KO mice (16). These studies portant roles in maintaining homeostasis of commensal microflora suggest that CCR10/ligands are not critically required for normal and neutralizing food-borne pathogens and toxins (1). In normal levels of IgA responses to commensal bacteria or pathogen in- mice, the majority of intestinal IgA-producing plasma cells origi- fection, and the functional importance of CCR10 in the intestinal nate in Peyer patches from naive B cells in response to the stim- IgA response is still unclear. By using a strain of CCR10-KO/ ulation of intestinal antigens (2). After undergoing the isotype EGFP-knock-in mice (17), we investigated expression and in- switch and affinity maturation in Peyer patches, IgA+ plasmablast volvement of CCR10 in intestinal IgA responses under homeo- cells migrate into effector sites such as the intestinal LP, where static conditions and during bacterial pathogen infection. In this they differentiate further to become mature IgA-producing report, we provide definite evidence that CCR10 is critical in the IMMUNOLOGY plasma cells. IgA-producing plasma cells are also generated in intestinal IgA response and memory maintenance. isolated lymphoid follicles (ILFs), the small follicles composed predominantly of B cells and scattered abundantly in small and Results large intestines of humans and mice (2–5). ILFs are formed only Defective Migration of CCR10-Deficient IgA+ Plasma Cells into Small after colonization of commensal bacteria in the intestines, sug- and Large Intestines. To understand how CCR10 is involved in gesting that they are involved in regulating the intestinal homeo- regulating IgA responses in the intestine, we used a strain of stasis of microflora (6). It was also reported that the intestinal LP itself could be a site for the in situ generation of IgA-producing plasma cells (7). These processes cooperate to maintain proper Author contributions: S.H. and N.X. designed research; S.H., K.Y., J.Y., and M.L. performed generation of IgA antibodies in the intestine. research; S.H., K.Y., and N.X. analyzed data; and S.H. and N.X. wrote the paper. Although generation of the intestinal IgA-producing plasma The authors declare no conflict of interest. cells is studied extensively, molecular mechanisms regulating the This article is a PNAS Direct Submission. IgA maintenance and memory responses are still poorly un- 1To whom correspondence should be addressed. E-mail: [email protected]. derstood. It was reported recently that the maintenance of intestinal See Author Summary on page 18205. fi IgA production is signi cantly different from that of systemic IgG This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. production (8). It was found that, in a germ-free condition, antigen- 1073/pnas.1100156108/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1100156108 PNAS | November 8, 2011 | vol. 108 | no. 45 | E1035–E1044 Downloaded by guest on September 25, 2021 CCR10-KO/EGFP-knock-in mice in which the coding region of ferred into WT mice. Notably, significantly fewer EGFP+IgA+ − enhanced GFP (EGFP) replaced most of the CCR10 coding re- cells of the CCR10EGFP/EGFP donor (CD45.1 CD45.2+) were re- gion from its translation start site down, allowing us to use the covered from large and small intestines of the recipients than those knocked-in EGFP as a reporter for endogenous CCR10 expres- of the CCR10+/EGFP donor (CD45.1+CD45.2+) 60 h after the sion (17). First, we determined effects of CCR10 KO on intestinal transfer (Fig. 1 C and D). These results suggest that CCR10 is IgA production under normal specific pathogen-free conditions. required for efficient migration of IgA+ cells into the intestines In heterozygous CCR10-KO/EGFP-knock-in (CCR10+/EGFP) and no other molecule could fully compensate for its function in − − mice, nearly all mature IgA+ plasma cells (B220 CD19 )of this process. Therefore, the apparently normal levels of intestinal intestines were EGFP+ (Fig. 1A), consistent with the previous IgA+ cells and antibodies in CCR10EGFP/EGFP mice result from report that they expressed CCR10 (9). Intestinal IgA+ plasma cells a compensation mechanism other than functional redundancy of of homozygous CCR10EGFP/EGFP were also EGFP+, and their any other homing receptor with CCR10. numbers were not different from those of WT (CCR10+/+)or CCR10+/EGFP mice (Fig. 1A). Mean fluorescence intensities of Enhanced Generation of IgA+ Cells Within Increased Numbers of ILFs EGFP signals in the IgA+ cells of CCR10EGFP/EGFP mice were two in CCR10EGFP/EGFP Mice. Onepossiblemechanism to compensate for times those of CCR10+/EGFP mice (Fig. 1A), suggesting that both the impaired intestinal localization of IgA+ cells in CCR10EGFP/EGFP alleles were coexpressed and the knocked-in EGFP could reliably mice is to increase their generation. ILFs, the dynamic B-cell–rich report CCR10 expression. Levels of total IgA antibodies in feces follicles in intestines, are likely a site for the compensational were similar in CCR10EGFP/EGFP, CCR10+/EGFP, and WT mice generation of IgA+ cells. Supporting this notion, there were sig- (Fig. 1B), consistent with the normal numbers of intestinal IgA+ nificantly more ILFs in intestines of CCR10EGFP/EGFP mice than plasma cells
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