Specific attachment of mesenteric IgA lymphoblasts to specialized endothelium of intestinal mucosa lamina propria capillaries

The bulk of IgA secreted in the gut is mostly contributed by locally dwelling plasma cells derived from B cells originating in the gut-associated lymphoid tissues (GALT). These IgA cells originate in Peyer's patches and recirculate, returning to the gut upon maturity. The precise mechanism of homing to secretory mucosae is to date not fully understood. It has been demonstrated, however, that specialized endothelium of small vascular spaces in peripheral nodes (PN) and endothelia of mucosal vessels are the site of receptor recognition for B and T cells. In their sojourn, IgA blasts have been shown to stop momentarily in mesenteric nodes (MN) before proceeding to their final destination, the lamina propria (LP) of the gut mucosa. They then develop into IgA-secreting plasma cells. In the present work, we show that IgA MN lymphoblasts, when compared to PN lymphoblasts, attach preferentially to LP venule and capillary endothelium, The B-cell maturation in the mesenteric lymph nodes, where IgA is the sole membrane-bound immunoglobulin, allows attachment of most of these cells. Our work suggests that the site of exit of IgA cells from the circulation are these specialized lamina propria venules and capillaries.     

Organ and isotype distribution of plasma cells producing specific antibody after oral immunization: evidence for a generalized secretory immune system.

Mice were induced to produce IgA antibodies against ferritin after oral immunization. Such antibodies were detected by immunofluorescence in plasma cells in the intestinal mucosa as well as in secretory sites located elsewhere, such as the lactating mammary gland, salivary gland, and respiratory tract. The observation suggested that cells immunized locally via the gut could home to distant secretory sites. To confirm this hypothesis, lymphocyte transfer studies were done with mesenteric node (MN) versus peripheral node (PN) cells from orally immunized donors into nonimmunized recipients. IgA anti-ferritin cells from MN homed to exocrine targets, whereas IgM and IgG anti-ferritin cells homed to PN. The findings overall support the concept of a generalized and interrelated secretory immune system.     

An immunohistochemical study of cells with surface and cytoplasmic immunoglobulins in situ in Peyer's patches and lamina propria of rat small intestine

The distribution of cells with surface and cytoplasmic immunoglobulins was studied in Peyer's patches (PP) and intestine of rats, using both frozen and paraffin sections, with a two-step peroxidase technique. Anti IgM, IgG, IgA and IgE sera were used. Surface staining was found within PP with all antisera used. Although the villi contained predominantly IgA plasma cells (PC), IgG PC and a few IgM and IgE PC were also found. Within PP, however, no IgA PC were found but IgM and IgG PC were present in all stages of development, mainly in the dome. PC of all types, but mostly IgA cells, were present in and around high endothelial venules (HEV). The results suggest that IgM and IgG PC precursors can develop to PC within PP whereas IgA precursors do not. PC appear to home to the gut preferentially via HEV.     

T-cell help for the IgA response: the function of T cells from different lymphoid organs in regulating the proportions of plasma cells expressing various isotypes

Differential distribution of IgA-specific primed Lyt 2- T cells (TH) in favor of gut-associated lymphoid tissue (GALT) has been proposed to account for the high proportion of IgA-producing plasma cells at mucosal versus nonmucosal sites. We find, however, that GALT TH primed enterically with sheep red blood cells (SRBC) contain no more help for IgA responses than peripheral lymph node (PN) TH primed subcutaneously. Moreover, GALT TH are only poorly primed by enterically administered soluble protein antigen and therefore provide less help for all isotypes than PN TH primed subcutaneously with the same antigen. On the other hand, supernatants of GALT TH stimulated with concanavalin A (Con A) in vitro do help higher IgA:IgG plaque-forming cell (PFC) ratios in cultures with 2,4, 6-trinitrophenyl-SRBC (TNP-SRBC) than supernatants from PN and spleen, indicating that, when appropriately stimulated, GALT TH are capable of promoting relatively higher IgA responses than TH from other sources. Responses elicited by either SRBC-primed TH or splenic Con A supernatants in the presence of TNP-SRBC contained higher IgA:IgG PFC ratios than those elicited by linked recognition in the presence of haptenated soluble protein carrier.     

The origin of the immunoglobulins in intestinal lymph of sheep.

Various immunoglobulins were labelled with radioactive iodine and their distribution between intestinal lymph and plasma followed in order to determine the origin of the immunoglobulins found in intestinal lymph. By comparing specific activities in plasma and lymph, it was computed that 25 percent of the IgG1 and IgG2 and 90 percent of the IgA in intestinal lymph were locally synthesised. The results suggest that virtually all of the IgA and a proportion of the IgG1 computed to be synthesised locally were derived from plasma cells of corresponding specificity in the lamina propria of the intestine.     

The wasted mutant mouse. I. An animal model of secretory IgA deficiency with normal serum IgA

The wasted (wst) mutation was recently described as a spontaneous, recessive mutation leading to pathologic changes affecting both the neurologic and the immune systems of wst/wst homozygotes, which presented symptoms analogous to those observed in patients with ataxia-telangiectasia (A.T.). We studied the IgA system of wst/wst mutants and their normal littermates to determine whether IgA deficiency commonly found in A.T. patients was also affecting these mutants. Interestingly, although IgA plasma cells were totally absent from their entire (small and large) intestine, their serum contained a normal level of IgA with a normal ratio of monomeric vs polymeric IgA. The absence of gut IgA plasma cells was not due to malnutrition and was not compensated by the appearance of cells secreting any other isotypes. Studies at the precursor cell level showed the absence of IgA-specific B cell precursors in the Peyer's patches, whereas sIgA B cells and IgA plasma cells were found in normal numbers in the spleen of wasted mice. These data suggest that secretory and serum IgA may comprise distinct systems and that the wasted mutant mouse is a potential model for the study of the physiology and regulation of IgA production.     

Determinants of the localization, magnitude, and duration of a specific mucosal IgA plasma cell response in enterically immunized rats

The origin and fate of specific IgA plasma cells in intestinal lamina propria were studied in rats immunized enterically with cholera toxin (CT). Our major goal was to define how an anti-CT response is focused and sustained at the site of antigen challenge. To distinguish antigen-dependent from antigen-independent mechanisms, CT exposure was restricted to defined portions of intestine and, in some studies, the distribution of antitoxin-containing plasma cells (ACC) was examined in nonimmune adoptive recipients of post-challenge thoracic duct lymphocytes. After enteric priming and challenge, ACC appeared throughout the gut, but were most numerous at the challenged site. About 25% of ACC appearing at the site of jejunal challenge were due to antigen-driven proliferation of memory cells within the lamina propria; the remainder arose elsewhere, apparently in mucosal follicles or mesenteric lymph nodes, and migrated systemically as antitoxin-containing plasmablasts before homing to the lamina propria. The homing of these migrating ACC precursors was not affected by mucosal exposure to CT, nor did they undergo appreciable antigen-driven division after arrival in gut lamina propria. However, homing was specific for the organ from which they arose, i.e., precursors arising from duodenal challenge homed selectively to jejunum, whereas those from colonic challenge homed to the colon. The organ specificity of homing was determined during the challenge response and was independent of the origin of memory cells participating in the response. The survival of migrating ACC precursors did not differ in segments of gut exposed or nonexposed to CT. However, CT exposure at the time of their migration evoked another secondary-type response, due to stimulation of comigrating memory cells, thus sustaining the secondary response at a high level. These results and those in a previous report identify important mechanisms that affect the localization, magnitude, and duration of a specific IgA response, at least in the intestine. These include: 1) organ-specific homing of migrating IgA plasmablasts, 2) antigen-driven generation of IgA plasma cells from memory cells within the lamina propria, 3) enhanced memory at the site of mucosal priming compared to that a distant mucosae, and 4) regeneration of memory cells during the secondary response.     

A monoclonal antibody specific for rat intestinal lymphocytes

A monoclonal antibody, RGL-1, was produced by fusion of NSI myeloma cells with spleen cells of a mouse immunized with isolated rat intraepithelial lymphocytes (IEL). SDS-PAGE analysis revealed that RGL-1 precipitated two major noncovalently bound chains of about m.w. 100,000 and 125,000, and a minor component of m.w. 200,000. Examination of both tissue sections and isolated cells indicated that RGL-1 stained the majority of the lamina propria lymphocytes and IEL but only very few cells (less than 2%) in the lymphoid organs and small numbers of lymphocytes in other mucosae. In the small intestine, RGL-1 stained lymphocytes with the helper (W3/25) as well as the cytotoxic/suppressor (OX8) phenotype. The antibody reacted with 95% of the granular IEL but with less than 0.1% of the blood large granular lymphocytes. Although mature IgA plasma cells in the lamina propria were RGL-1-, some large IgA-containing cells were weakly positive. In the gut-associated lymphoid tissues (GALT), studies combining immunofluorescence and autoradiography indicated that 56 and 73% of rapidly dividing cells of mesenteric lymph nodes and of thoracic duct lymph (TDL) stained with RGL-1, respectively. In addition, 90 to 100% of the IgA-containing blasts of MLN and 75% of those of TDL were labeled by RGL-1. In contrast, rapidly dividing cells of spleen and of peripheral lymph nodes did not stain with RGL-1. Because RGL-1 can be demonstrated on both intestinal lymphocytes and their immediate precursors in the GALT, its expression may be related to the homing of lymphocytes into the gut mucosa.     

Fate of H2-activated T lymphocytes in syngeneic hosts. I. Fate in lymphoid tissues and intestines traced with 3H-thymidine, 125I-deoxyuridine and 51chromium.

Information was sought on the fate of T cells activated to H2 determinants in vivo. The cells were obtained from thoracic duct lymph of irradiated F₁ mice injected with parental strain T cells. The fate of the lymph-borne cells—nearly all of which were donor-cell-derived, host-reactive T blasts (T.TDL)—was studied by labelling the cells with either ³HTdR, ¹²⁵IUdR or ⁵¹Cr and transferring them to syngeneic mice.A large proportion of T.TDL (20%) homed to the intestines on transfer. In the small intestine 40% of the cells were located in Peyer's patches; this was lower than with normal TDL (>70%) but higher than with a population of B (θ-negative) blasts (<10%). Some T.TDL were situated within the surface epithelium of the gut. Studies with ⁵¹Cr-labelled cells suggested that a proportion of these cells entered the gut lumen.T.TDL also homed to the large intestine but only when derived from a small inoculum of T cells. T.TDL derived from a large dose of T cells homed preferentially to the small intestine; in this respect they resembled B blasts.Homing to the intestines seemed a general property of T cells activated to transplantation antigens. It was observed irrespective of whether the T.TDL were activated against H2 determinants, M-locus determinants or H2-plus M-locus determinants.Most T.TDL died in the lymphoid tissues within 1–2 weeks of transfer. This conclusion was derived from comparative studies of (a) autoradiographs prepared from recipients of ³HTdR-labelled T.TDL and TDL and (b) the migratory properties of labelled cells harvested from recipients of ⁵¹Cr-labelled T.TDL, normal TDL and irradiated TDL. Rapid clearance of radioactivity from recipients of T.TDL labelled with ¹²⁵IUdR was consistent with this conclusion. Adequate control experiments with this isotope were not possible, however, because attempts to label long-lived lymphocytes (TDL) with ¹²⁵IUdR were unsuccessful.Studies with a variety of cells labelled with ¹²⁵IUdR indicated that a proportion of the label was excreted via the stomach. In certain situations, e.g., in mice with tied renal vessels, extremely high counts (>40% of the injected counts) appeared in the stomach contents.     

Selective chemotaxis of subsets of B lymphocytes from gut-associated lymphoid tissue and its implications for the recruitment of mucosal plasma cells

As they differentiate, precursor cells from the gut-associated lymphoid tissue are known to travel via the lymphatic system to the blood and then preferentially to home to various mucosal and exocrine sites such as the lamina propria of the gut and the lactating mammary gland, where they give rise to IgA-secreting plasma cells. The present study, directed at the mechanism by which the circulating precursors of mucosal IgA plasma cells selectively lodge in characteristic locations, explored the hypothesis that such homing is due to a locally produced chemotactic factor and that milk might be a source of such a factor. Subsets of lymphocytes bearing particular surface markers and purified by panning from lymph nodes of mice were examined in a micropore chemotaxis assay to search for the presence of chemotactic activity in mouse milk. The globulin fraction of whey was shown to contain a nondialyzable factor that is chemotactic for IgA (and also IgG)-positive lymphocytes when these are obtained from mesenteric lymph nodes as a source of mucosal-associated lymphoid tissue. Lymphocytes from peripheral lymph nodes, nonmucosal associated, were unaffected as were surface IgM-positive lymphocytes and T lymphocytes obtained from mesenteric nodes. Chemotactic activity for IgA lymphocytes was undetectable in mouse serum. The data are consistent with the idea that precursors of mucosal IgA plasma cells home to mucosal and exocrine sites in response to a specific chemotactic factor elaborated by local differentiated epithelial cells.     

The effects of IL-4 and IL-5 on the IgA response by murine Peyer's patch B cell subpopulations

IL-5 has been shown to specifically enhance IgA secretion in LPS-stimulated splenic B cell cultures. Maximum enhancement of IgA in such cultures, however, requires IL-4 in addition to IL-5. Because the Peyer's patches (PP), compared with spleen and lymph nodes, are enriched for precursors of IgA-secreting cells, we tested whether IL-4 and IL-5 would have a more profound effect on IgA secretion by polyclonally stimulated PP cells than spleen cells. The combination of IL-4 and IL-5 causes a comparable enhancement of IgA secretion in both LPS-stimulated PP and splenic B cell cultures. The majority of IgA secreted in LPS-stimulated PP cell cultures is derived from the sIgA- population. Furthermore, the binding high level of peanut agglutinin, germinal center subpopulation of PP cells is essentially nonresponsive to LPS, even in the presence of lymphokines; the majority of secreted IgA in these cultures is derived from the binding low level of peanut agglutinin population. In contrast to LPS-stimulated cultures, PP B cells secrete considerably more IgA than splenic B cells when polyclonally stimulated by a clone of autoreactive T cells in the presence of IL-4 and IL-5. The majority of IgA made by T cell-stimulated PP cell cultures is derived from the sIgA+ population. In these cultures, sIgA- PP cells and spleen cells secrete comparable levels of IgA and other non-IgM isotypes suggesting that sIgA- PP B cells are similar to splenic B cells in their potential to switch to IgA. In T cell-stimulated cultures the majority of IgA as well as of all other isotypes is also derived from the nongerminal center, binding low level of peanut agglutinin population.     

Cutting edge: Langerin+ dendritic cells in the mesenteric lymph node set the stage for skin and gut immune system cross-talk

Topical transcutaneous immunization (TCI) presents many clinical advantages, but its underlying mechanism remains unknown. TCI induced Ag-specific IgA Ab-secreting cells expressing CCR9 and CCR10 in the small intestine in a retinoic acid-dependent manner. These intestinal IgA Abs were maintained in Peyer's patch-null mice but abolished in the Peyer's patch- and lymph node-null mice. The mesenteric lymph node (MLN) was shown to be the site of IgA isotype class switching after TCI. Unexpectedly, langerin(+)CD8alpha(-) dendritic cells emerged in the MLN after TCI; they did not migrate from the skin but rather differentiated rapidly from bone marrow precursors. Depletion of langerin(+) cells impaired intestinal IgA Ab responses after TCI. Taken together, these findings suggest that MLN is indispensable for the induction of intestinal IgA Abs following skin immunization and that cross-talk between the skin and gut immune systems might be mediated by langerin(+) dendritic cells in the MLN.     

In vitro regulation of IgA subclass synthesis. II. The source of IgA2 plasma cells

In vitro regulation of IgA subclass synthesis was investigated in pokeweed mitogen (PWM)-stimulated cultures of peripheral blood lymphocytes. In past experiments we have demonstrated that 50% of the IgA plasma cells derived from PWM-stimulated cultures are positive for IgA1 and 50% are positive for IgA2. This observation is surprising because approximately 80% of the IgA B cells in the peripheral circulation bear IgA1 and 20% bear IgA2. To determine if the shift toward IgA2 predominance in PWM-stimulated cultures might be due to an enriched source for IgA2 plasma cells from a precursor pool of immature B cells, we used panning techniques to separate immature precursors that express surface IgM (sIgM+) from mature precursors that no longer express IgM (sIgM-). These separated B cells were cultured with equal numbers of T cells and PWM for 7 days. In all 10 experiments there was an enrichment for IgA2 in the sIgM+ cultures; 55 +/- 9.6% of the total IgA plasma cells were positive for IgA2 in the sIgM+ cultures vs 38 +/- 6.3% in the sIgM- cultures (p less than 0.001). These results indicate that both sIgM+ and sIgM- cells can give rise to IgA plasma cells in PWM-stimulated cultures and that there is an enrichment for IgA2 precursors in the sIgM+ population. Other possible regulatory mechanisms were also investigated. To determine if there was isotype switching from IgA1 to IgA2, monoclonal anti-IgA1 antibodies were added to PWM cultures. These antibodies resulted in a mean suppression of IgA1 plasma cell production of 82% with a concomitant 45% suppression of total IgA but only 4.6% suppression of IgA2. These results make it unlikely that IgA2 plasma cells in PWM-stimulated cultures are derived from cells that initially produced IgA1. To investigate the possibility that one IgA subclass might be more T cell dependent than the other, T and B cells were separated and B cells were reconstituted with T cells in ratios that varied from 1:10 to 10:1 or with irradiated T cells. These procedures did not alter the proportion of IgA plasma cells positive for IgA1 or IgA2, indicating that the two subclasses do not differ in their response to T cell signals in PWM-stimulated cultures.     

Immunoglobulin isotypes in plasma cells of normal and athymic mice.

The distribution of plasma cells was determined in various lymphoid tissues and exocrine glands of athymic (nude) mice. Compared to values for normal mice, the total number of plasma cells in organs of athymic mice showed a variable decrease as follows: 0%, small intestine; 29%, respiratory tree; 33%, spleen; 50%, lymph nodes; 75%, lactating mammary gland; 85%, Peyer's patches; and 90%, parotid gland. Plasma cells containing IgG₁ or IgA showed the greatest decrease, whereas IgM-containing plasma cells were actually increased by 100% or more in most organs. In exocrine glands the absolute deficit of IgA-containing plasma cells was most marked in the parotid and lactating mammary gland, and least in the small intestine. All lymphoid tissues had a striking deficit in the absolute numbers of IgA as well as IgG, plasma cells. Total plasma cell numbers and their isotype distribution were similar for BALB/c +/+ (homozygous) and +/nu (heterozygous) mice.     

Random recirculation of small T lymphocytes from thoracic duct lymph in the mouse

The migration of ⁵¹Cr-labeled nylon-wool separated mouse thoracic duct T cells has been followed in order to determine whether there is a circulation of small (nondividing) T cells through the small intestine. Approximately 6% of the injected dose of T-TDL localized in the small intestine (minus Peyer's patches). Experiments revealed that this gut-localizing cell population consisted almost entirely, if not exclusively, of lymphoblasts present in mouse T-TDL. When lymphoblasts and small lymphocytes from mouse T-TDL were separated by velocity sedimentation, and the migration of separated fractions was studied, we found large cells (66% blasts) migrated well to the gut but poorly to the lymph nodes, whereas small cells (2% blasts) showed minimal migration to the gut but localized randomly in lymph nodes and spleen. The in vivo distribution of small cells from T-TDL was similar to that of T-PLN. Furthermore, the recirculatory patterns of both ⁵¹Cr-labeled T-TDL and T-PLN were found to be identical as accessed by their rate of recovery in the thoracic duct lymph of recipient mice. These results support the notion that the vast majority of T-TDL and T-PLN are part of a common pool of recirculating T cells which recirculate randomly through lymph nodes and spleen and not the small intestine.     

Mechanisms involved in down-regulation of intestinal IgA in rats by high cocoa intake

Previous studies have shown that rat intestinal immunoglobulin A (IgA) concentration and lymphocyte composition of the intestinal immune system were influenced by a highly enriched cocoa diet. The aim of this study was to dissect the mechanisms by which a long-term high cocoa intake was capable of modifying gut secretory IgA in Wistar rats. After 7 weeks of nutritional intervention, Peyer's patches, mesenteric lymph nodes and the small intestine were excised for gene expression assessment of IgA, transforming growth factor β, C-C chemokine receptor-9 (CCR9), interleukin (IL)-6, CD40, retinoic acid receptors (RARα and RARβ), C-C chemokine ligand (CCL)-25 and CCL28 chemokines, polymeric immunoglobulin receptor and toll-like receptors (TLR) expression by real-time polymerase chain reaction. As in previous studies, secretory IgA concentration decreased in intestinal wash and fecal samples after cocoa intake. Results from the gene expression showed that cocoa intake reduced IgA and IL?6 in Peyer's patches and mesenteric lymph nodes, whereas in small intestine, cocoa decreased IgA, CCR9, CCL28, RARα and RARβ. Moreover, cocoa-fed animals presented an altered TLR expression pattern in the three compartments studied. In conclusion, a high-cocoa diet down-regulated cytokines such as IL-6, which is required for the activation of B cells to become IgA-secreting cells, chemokines and chemokine receptors, such as CCL28 and CCR9 together with RARα and RARβ, which are involved in the gut homing of IgA-secreting cells. Moreover, cocoa modified the cross-talk between microbiota and intestinal cells as was detected by an altered TLR pattern. These overall effects in the intestine may explain the intestinal IgA down-regulatory effect after the consumption of a long-term cocoa-enriched diet.     

Simultaneous induction of antigen-specific IgA helper T cells and IgG suppressor T cells in the murine Peyer's patch after protein feeding

The effects of feeding the dietary protein antigen, ovalbumin (OVA), on OVA-specific IgG and IgA immune responses involving Peyer's patches (PP) and mesenteric lymph nodes (MLN) were examined. Mice were administered soluble OVA by gastric intubation. One to 3 days later, PP, MLN, or spleen cells from these donor mice were adoptively transferred into normal syngeneic recipients. After two subsequent immunizations, spleens from the recipient mice were assayed for IgA and IgG anti-OVA plaque-forming cell (PFC) responses. None of the tissues from normal (unfed) mice had the inherent ability to alter recipients' IgG or IgA PFC responses. Within 1 day of OVA feeding, however, cells were generated in the PP that could augment recipients' IgA anti-OVA PFC responses and suppress IgG PFC responses. Three days after OVA feeding, these cells were present in MLN as well, and whereas the IgG suppressor cell also appeared to migrate to spleen, the IgA helper cell did not. The cells mediating antigen-specific IgG suppression and IgA help were both T cells but could be distinguished by surface phenotype. We therefore conclude that protein feeding induces differential, isotype-specific immunoregulation in gut-associated lymphoid tissues, part of which is mediated by an antigen-specific IgA helper T cell.     

Evidence of extensive lymphocyte death in sheep Peyer's patches. II. The number and fate of newly-formed lymphocytes that emigrate from Peyer's patches

The emigration of newly produced lymphocytes from Peyer's patches (PP) of lambs was studied. Mesenteric lymph nodes (MLN) were excised from most animals a few weeks after birth, and then at 8 to 10 wk of age, the dividing cells in 3 to 4 m of the small intestine were labeled in situ with [3H]thymidine. An extracorporeal perfusion system was used to restrict the 15-min period of labeling to the perfused lengths of intestine, which included either the large continuous ileal PP or a number of smaller jejunal PP. One or 3 days later, the number of labeled cells in the perfused tissue and in other lymphoid organs was studied by autoradiography. In the perfused tissues, labeled lymphocytes accounted for 63.7% of ileal PP cells by 1 day and for 86.7% by 3 days compared with only 9.6% of lymphocytes in the perfused MLN. Labeled lymphoid cells in the perfused PP were nearly all in the follicles. Labeled lymphocytes that must have been produced in the segments of ileum or jejunum at the time of the perfusion, subsequently emigrated via the lymphatics, and were identified in the spleen, MLN, other lymph nodes, blood, jejunal PP, and at a lower frequency in the thymus, nonperfused ileal PP, and bone marrow. In lymph nodes, spleen, and nonperfused PP, more than 80% of the immigrant newly formed PP-derived cells were small- and medium-sized lymphocytes, and about 15% were large lymphocytes. The nature of the labeled cells in the lamina propria of the nonperfused small intestine was quite different in that approximately 50% were plasma cells as early as 24 hr after the cells were born in the perfused gut. It is proposed that terminal B cell differentiation was most likely initiated within the PP in response to the entry of antigen. It was estimated that at both 1 and 3 days after perfusion there were about 100 times more labeled cells in the perfused ileal PP than could be accounted for by emigration to other organs. It was concluded that these results provide additional support for the view that PP in lambs produce a tremendous number of lymphocytes, but relatively few leave their site of production; most apparently die in situ.     

Sphingosine 1-phosphate regulates the egress of IgA plasmablasts from Peyer's patches for intestinal IgA responses

It is well established that Peyer's patches (PPs) are sites for the differentiation of IgA plasma cell precursors, but molecular and cellular mechanisms in their trafficking remain to be elucidated. In this study, we show that alterations in type 1 sphingosine 1-phosphate (S1P) receptor expression during B cell differentiation in the PPs control the emigration of IgA plasma cell precursors. Type 1 S1P receptor expression decreased during the differentiation of IgM(+)B220(+) B cells to IgA(+)B220(+) B cells, but recovered on IgA(+)B220(-) plasmablasts for their emigration from the PPs. Thus, IgA(+)B220(-) plasmablasts migrated in response to S1P in vitro. Additionally, IgA(+) plasmablasts selectively accumulated in lymphatic regions of PPs when S1P-mediated signaling was disrupted by FTY720 treatment. This accumulation of IgA(+) plasmablasts in the PPs led to their reduction in the intestinal lamina propria and simultaneous impairment of Ag-specific intestinal IgA production against orally administered Ag. These findings suggest that S1P regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.