倉島 洋介

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 tracking 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 SIP in vitro. Additionally, IgA(+) plasmablasts selectively accumulated in lymphatic regions of PPs when SIP-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 SIP regulates the retention and emigration of PP B cells and plays key roles in the induction of intestinal IgA production.

It is well established that intraepithelial T lymphocytes ( IELs) are derived from conventional single- positive ( SP) thymocytes, as well as unconventional double- negative ( DN) thymocytes and CD103(+) CD8 alpha beta recent thymic emigrants ( RTEs). We show that IELs can be divided into two groups according to their dependency on sphingosine 1- phosphate ( S1P) for trafficking into the intestines. CD4 or CD8 alpha beta naive lymphocytes originating from SP thymocytes express high levels of type 1 S1P receptor ( S1P 1), and their preferential migration into the large intestine is regulated by S1P. In contrast, RTEs migrate exclusively into the small intestine, whereas DN thymic IEL precursors expressing either TCR alpha beta or TCR gamma delta migrate into both the small and large intestines. S1P does not play a role in the migration pathways of these unconventional thymic IEL precursors. Thus, down- regulation of S1P(1) expression or disruption of the S1P gradient halted conventional CD4 or CD8 alpha beta IEL trafficking into the intestines, but did not affect the trafficking of unconventional thymic IEL precursors. These data are the first to demonstrate that a lipid- mediated system discriminates IELs originating from conventional and unconventional thymic precursors.

Sphingosine I-phosphate (SIP) has been proposed as a regulator of lymphocyte trafficking, but its role in mucosa-associated diseases, such as in food allergies, remains to be elucidated. To examine the role of SIP in allergic diseases in the intestine, we used a Th2 cell-mediated Ag-specific allergic diarrhea model and demonstrated that type 1 SIP receptor (S1P(1)) expression was preferentially associated with pathogenic CD4(+) T cells for the development of allergic reactions. Consistent with this demonstration, treatment with FTY720, a modulator of the SIP,, prevented allergic diarrhea by inhibiting the migration of systemically primed pathogenic CD4(+) T cells induced by oral challenge with allergen into the large intestine. In addition, FTY720 hampered mast cell infiltration into the large intestine, whereas eosinophil infiltration into the large intestine and total and allergen-specific serum IgE production were comparable between mock- and FTY720-treated groups. These results suggest that modulation of the SIP-mediated pathway to inhibit the migration of pathogenic CD4(+) T cells and mast cells into the large intestine could be a novel strategy for preventing allergic diarrhea.

Sphingosine 1-phosphate (S1P) is known to play a pivotal role in the regulation of lymphocyte emigration from organized lymphoid tissues such as the peripheral lymph nodes and thymus, but its immunologic role in unorganized and diffused tissues remains to be elucidated. Here we show that the trafficking of peritoneal B cells is principally regulated by S1P. All peritoneal B cells including B1a, B1b, and B2 B cells express comparable levels of the type 1 S1P receptor. Thus, treatment with FTY720, an S1P receptor modulator, caused the rapid disappearance of peritoneal B cells by inhibiting both their emigration from parathymic lymph nodes and their recirculation from the blood into the peritoneal cavity without affecting their progenitor populations. These changes did not affect natural plasma antibody production or phosphorylcholine (PC)-specific antibody production in serum after peritoneal immunization with heat-killed Streptococcal pneumoniae (R36A). However, FTY720 dramatically reduced peritoneal B cell-derived natural intestinal secretory IgA production without affecting the expression of J-chain and polyimmunoglobulin receptors. Additionally, FTY720 impaired the generation of PC-specific fecal IgA responses after oral immunization with R36A. These findings point to a pivotal role for S1P in connecting peritoneal B cells with intestinal B-cell immunity (C) 2007 by The American Society of Hematology.