Intestinal intraepithelial lymphocytes prevent pathogen‐driven inflammation and regulate the Smad/T‐bet pathway of lamina propria CD4<sup>+</sup> T cells

Self Cite

120

111

TLRs expressed by a variety of cells, including epithelial cells, B cells, and dendritic cells, are important initiators of the immune response following stimulation with various microbial products. Several of the TLRs require the adaptor protein, MyD88, which is an important mediator for the immune response following Toxoplasma gondii infection. Previously, TLR9-mediated innate immune responses were predominantly associated with ligation of unmethylated bacterial CpG DNA. In this study, we show that TLR9 is required for the Th1-type inflammatory response that ensues following oral infection with T. gondii. After oral infection with T. gondii, susceptible wild-type (WT; C57BL/6) but not TLR9−/− (B6 background) mice develop a Th1-dependent acute lethal ileitis; TLR9−/− mice have higher parasite burdens than control WT mice, consistent with depressed IFN-γ-dependent parasite killing. A reduction in the total T cell and IFN-γ-producing T cell frequencies was observed in the lamina propria of the TLR9−/− parasite-infected mice. TLR9 and type I IFN production was observed by cells from infected intestines in WT mice. TLR9 expression by dendritic cell populations is essential for their expansion in the mesenteric lymph nodes of infected mice. Infection of chimeric mice deleted of TLR9 in either the hemopoietic or nonhemopoietic compartments demonstrated that TLR9 expression by cells from both compartments is important for efficient T cell responses to oral infection. These observations demonstrate that TLR9 mediates the innate response to oral parasite infection and is involved in the development of an effective Th1-type immune response.

Section: Tlr9 Expressed By the Cells From Both The Hemopoietic And Nomentioning

confidence: 59%

“…CD4 T cells (CD45RB high , CD25 Ϫ ), isolated from the lamina propria, were identified as a major player in the inflammatory process (41). Following infection, CD4…”

Section: Discussionmentioning

confidence: 99%

TLR9 Is Required for the Gut-Associated Lymphoid Tissue Response following Oral Infection of Toxoplasma gondii

Minns

Ménard

Foureau

et al. 2006

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120

111

“…Myeloid DCs isolated from murine PPs produced high levels of IL-10 and induced naive T cells to differentiate into cells that produced much higher levels of IL-10 than T cells primed with any other DC subset (36). PP DC-mediated induction of IL-10-producing CD4 ϩ T cells (37,38), and expression of TGF-␤ in the lung and gastrointestinal mucosae, play a particularly important role in maintaining local tolerance and homeostasis (37,39,40). Similarly, oral delivery of exogenous recombinant SIgA and SIgA-based immune complexes contribute to orchestrate noninflammatory responses (this study) by triggering secretion of IL-10 and TGF-␤ by mucosal CD4 ϩ T cells (10).…”

Section: Discussionmentioning

confidence: 99%

Secretory IgA Mediates Bacterial Translocation to Dendritic Cells in Mouse Peyer’s Patches with Restriction to Mucosal Compartment

Kadaoui

Corthésy

2007

150

127

In addition to fulfilling its function of immune exclusion at mucosal surfaces, secretory IgA (SIgA) Ab exhibits the striking feature to adhere selectively to M cells in the mouse and human intestinal Peyer’s patches (PPs). Subsequent uptake drives the SIgA Ab to dendritic cells (DCs), which become partially activated. Using freshly isolated mouse DCs, we found that the interaction with SIgA was tissue and DC subtype dependent. Only DCs isolated from PPs and mesenteric lymph nodes interacted with the Ab. CD11c+CD11b+ DCs internalized SIgA, while CD11c+CD19+ DCs only bound SIgA on their surface, and no interaction occurred with CD11c+CD8α+ DCs. We next examined whether SIgA could deliver a sizeable cargo to PP DCs in vivo by administering SIgA-Shigella flexneri immune complexes into a mouse ligated intestinal loop containing a PP. We found that such immune complexes entered the PPs and were internalized by subepithelial dome PP DCs, in contrast to S. flexneri alone that did not penetrate the intestinal epithelium in mice. Dissemination of intraepithelial S. flexneri delivered as immune complexes was limited to PPs and mesenteric lymph nodes. We propose that preexisting SIgA Abs associated with microbes contribute to mucosal defense by eliciting responses that prevent overreaction while maintaining productive immunity.

“…cDNA was subjected to real-time PCR by using a ABI 7000 sequence detector (Applied Biosystems) (36 30 pmol of the ␣-subunit of the epithelial sodium channel (ENaC), and 35 pmol of the cystic fibrosis transmembrane conductance regulator (CFTR) primers. The primers used for MyD88, ␣-ENaC, and CFTR were the same as those previously described (33,37).…”

Section: Real-time and Rt-pcrmentioning

confidence: 99%

Renal Collecting Duct Epithelial Cells React to Pyelonephritis-Associated Escherichia coli by Activating Distinct TLR4-Dependent and -Independent Inflammatory Pathways

Chassin

Goujon

Darche³

et al. 2006

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119

156

TLR4 plays a central role in resistance to pyelonephritis caused by uropathogenic Escherichia coli (UPEC). It has been suggested that renal tubule epithelial cells expressing TLRs may play a key role in inflammatory disorders and in initiating host defenses. In this study we used an experimental mouse model of ascending urinary tract infection to show that UPEC isolates preferentially adhered to the apical surface of medullary collecting duct (MCD) intercalated cells. UPEC-infected C3H/HeJ (Lpsd) mice carrying an inactivating mutation of tlr4 failed to clear renal bacteria and exhibited a dramatic slump in proinflammatory mediators as compared with infected wild-type C3H/HeOuJ (Lpsn) mice. However, the level of expression of the leukocyte chemoattractants MIP-2 and TNF-α still remained greater in UPEC-infected than in naive C3H/HeJ (Lpsd) mice. Using primary cultures of microdissected Lpsn MCDs that expressed TLR4 and its accessory molecules MD2, MyD88, and CD14, we also show that UPECs stimulated both a TLR4-mediated, MyD88-dependent, TIR domain-containing adaptor-inducing IFN-β-independent pathway and a TLR4-independent pathway, leading to bipolarized secretion of MIP-2. Stimulation by UPECs of the TLR4-mediated pathway in Lpsn MCDs leads to the activation of NF-κB, and MAPK p38, ERK1/2, and JNK. In addition, UPECs stimulated TLR4-independent signaling by activating a TNF receptor-associated factor 2-apoptosis signal-regulatory kinase 1-JNK pathway. These findings demonstrate that epithelial collecting duct cells are actively involved in the initiation of an immune response via several distinct signaling pathways and suggest that intercalated cells play an active role in the recognition of UPECs colonizing the kidneys.