The intestinal cell types responsible for defense against pathogenic organisms remain incompletely characterized. Here we identify a subset of CD11c(hi)CD11b(hi) lamina propria dendritic cells (LPDCs) that expressed Toll-like receptor 5 (TLR5) in the small intestine. When stimulated by the TLR5 ligand flagellin, TLR5(+) LPDCs induced the differentiation of naive B cells into immunoglobulin A-producing plasma cells by a mechanism independent of gut-associated lymphoid tissue. In addition, by a mechanism dependent on TLR5 stimulation, these LPDCs promoted the differentiation of antigen-specific interleukin 17-producing T helper cells and type 1 T helper cells. Unlike spleen DCs, the LPDCs specifically produced retinoic acid, which, in a dose-dependent way, supported the generation and retention of immunoglobulin A-producing cells in the lamina propria and positively regulated the differentiation interleukin 17-producing T helper cells. Our findings demonstrate unique properties of LPDCs and the importance of TLR5 for adaptive immunity in the intestine.

Salmonella sneaks past security C ertain gut cells can leave resident bacteria alone but respond selectively to invaders. Satoshi Uematsu, Shizuo Akira, and colleagues (Osaka University, Japan) suggest that gut cells achieve this differentiation by using a special, pathogen-specifi c receptor called the Toll-like receptor 5 (TLR5). But the pathogenic Salmonella typhimurium turns the situation around: events triggered by the special receptor help the bug to invade its host. TLRs, which are expressed on professional antigen-presenting cells, recognize common pathogen-associated molecules and trigger innate immunity. TLR5 on dendritic cells recognizes bacterial fl agellin protein in vitro, but its function in vivo was previously unknown. Akira's team found that TLR5 mRNA was highly expressed in the mouse intestine particularly in a specifi c subpopulation of antigen-presenting lamina propria cells (CD11c + LPCs). In these cells, TLR5 was necessary for bacterial fl agellin to induce infl ammatory cytokines, yet when the team infected TLR5 −/− mice with Salmonella, a fl agellated bacterium, these mice were unexpectedly resistant to the bug. It was not, however, invasion of the CD11c + LPCs that showed a difference. In the gut, Salmonella invaded the CD11c + LPCs in both TLR5 +/+ and TLR5 −/− mice. However, in the TLR5 −/− mice, fewer bacteria-laden CD11c + LPCs moved from the intestinal tract to the mesenteric lymph nodes, probably because the LPCs failed to be activated by the bacteria. These mice had more resistance to systemic infection-fewer bacteria reached their livers and spleens-but it is not yet clear whether a similar tactic of TLR5 blocking would work in humans.

Although dendritic cells (DCs) located in the small intestinal lamina propria (LP-DCs) migrate to mesenteric lymph nodes (MLNs) constitutively, it is unclear which chemokines regulate their trafficking to MLNs. In this study we report that LP-DCs in unperturbed mice require CCR7 to migrate to MLNs. In vitro, LP-DCs expressing CCR7 migrated toward CCL21, although the LP-DCs appeared morphologically and phenotypically immature. In MLNs, DCs bearing the unique LP-DC phenotype (CD11chighCD8αintCD11blowαLlowβ7high and CD11chighCD8α−CD11bhighαLlowβ7high) were abundant in wild-type mice, but were markedly fewer in CCL19-, CCL21-Ser-deficient plt/plt mice and were almost absent in CCR7-deficient mice, indicating the critical importance of CCR7 in LP-DC trafficking to MLNs. Interestingly, CCR7+ DCs in MLNs with the unique LP-DC phenotype had numerous vacuoles containing cellular debris in the cytoplasm, although MLN-DCs themselves were poorly phagocytic, suggesting that the debris was derived from the LP, where the LP-DCs ingested apoptotic intestinal epithelial cells (IECs). Consistent with this, LP-DCs ingested IECs vigorously in vitro. By presenting IEC-associated Ag, the LP-DCs also induce T cells to produce IL-4 and IL-10. Collectively, these results strongly suggest that LP-DCs with unique immunomodulatory activities migrate to MLNs in a CCR7-dependent manner to engage in the presentation of IEC-associated Ags acquired in the LP.

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Interleukin-2 (IL-2) binds to two distinct receptor molecules, the IL-2 receptor alpha (IL-2R alpha, p55) chain and the newly identified IL-2 receptor beta (IL-2R beta, p70-75) chain. The cDNA encoding the human IL-2R beta chain has now been isolated. The overall primary structure of the IL-2R beta chain shows no apparent homology to other known receptors. Unlike the IL-2R alpha chain, the IL-2R beta chain has a large cytoplasmic region in which a functional domain (or domains) mediating an intracellular signal transduction pathway (or pathways) may be embodied. The cDNA-encoded beta chain binds and internalizes IL-2 when expressed on T lymphoid cells but not fibroblast cells. Furthermore, the cDNA gives rise to the generation of high-affinity IL-2 receptor when co-expressed with the IL-2R alpha chain cDNA.