Toll-like Receptors Activate Innate and Adaptive Immunity by using Dendritic Cell-Intrinsic and -Extrinsic Mechanisms

Hou, Baidong; Reizis, Boris; DeFranco, Anthony L.

doi:10.1016/j.immuni.2008.05.016

Cited by 329 publications

(345 citation statements)

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“…To test this idea, we generated mice with an epithelial cell-specific deletion of MyD88 (MyD88 ΔIEC ). We crossed mice carrying the epithelial cell-restricted Villin-Cre transgene (15) with mice harboring a loxP-flanked MyD88 allele (MyD88 fl/fl ) (16). This yielded progeny with an epithelial cellspecific MyD88 deletion (Fig.…”

Section: Resultsmentioning

confidence: 99%

γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface

Ismail

Severson

Vaishnava³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The mammalian gastrointestinal tract harbors thousands of bacterial species that include symbionts as well as potential pathogens. The immune responses that limit access of these bacteria to underlying tissue remain poorly defined. Here we show that γδ intraepithelial lymphocytes (γδ IEL) of the small intestine produce innate antimicrobial factors in response to resident bacterial "pathobionts" that penetrate the intestinal epithelium. γδ IEL activation was dependent on epithelial cell-intrinsic MyD88, suggesting that epithelial cells supply microbe-dependent cues to γδ IEL. Finally, γδ T cells protect against invasion of intestinal tissues by resident bacteria specifically during the first few hours after bacterial encounter, indicating that γδ IEL occupy a unique temporal niche among intestinal immune defenses. Thus, γδ IEL detect the presence of invading bacteria through cross-talk with neighboring epithelial cells and are an essential component of the hierarchy of immune defenses that maintain homeostasis with the intestinal microbiota.antibacterial defense | mucosal immunity | microbiota

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Section: Resultsmentioning

confidence: 99%

γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface

Ismail

Severson

Vaishnava³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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270

248

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“…Mice carrying a floxed Myd88 allele [Myd88 fl/fl , CBy.129P2(B6)-Myd88 tm1Defr /J] were generated as described previously (2,5) and backcrossed to the C57BL/6 background for at least 10 generations. C57BL/6 backcrossed Mb1-Cre (70) and CD11c-Cre (71) mice were crossed to Myd88 fl/fl mice to generate mice deleted for Myd88 selectively in B cells or DCs, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Recognition of infection by TLRs shapes adaptive immunity by directing dendritic cells (DCs) to activate naive T cells (1)(2)(3), by directing T helper (T H ) 1 and T H 17 polarization of effector T cells (3,4), and by promoting B-cell activation and terminal differentiation to antibody-secreting plasma cells (5,6).…”

mentioning

confidence: 99%

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

Rookhuizen

DeFranco

2014

Proc. Natl. Acad. Sci. U.S.A.

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Recent studies have demonstrated important roles of nucleic acidsensing Toll-like receptors (TLRs) in promoting protective antibody responses against several viruses. To dissect how recognition of nucleic acids by TLRs enhances germinal center (GC) responses, mice selectively deleted for myeloid differentiation primaryresponse protein 88 (MyD88) in B cells or dendritic cells (DCs) were immunized with a haptenated protein antigen bound to a TLR9 ligand. TLR9 signaling in DCs led to greater numbers of follicular helper T (T FH ) cells and GC B cells, and accelerated production of broad-affinity antihapten IgG. In addition to modulating GC selection by increasing inducible costimulator (ICOS) expression on T FH cells and reducing the number of follicular regulatory T cells, MyD88-dependent signaling in B cells enhanced GC output by augmenting a class switch to IgG2a, affinity maturation, and the memory antibody response. Thus, attachment of a TLR9 ligand to an oligovalent antigen acted on DCs and B cells to coordinate changes in the T-cell compartment and also promoted B cell-intrinsic effects that ultimately programmed a more potent GC response.T he ability of the innate immune system to survey infection relies on pattern recognition receptors, such as Toll-like receptors (TLRs), that signal through myeloid differentiation primary-response protein 88 (MyD88) upon recognition of pathogen-associated molecular patterns (PAMPs). Recognition of infection by TLRs shapes adaptive immunity by directing dendritic cells (DCs) to activate naive T cells (1-3), by directing T helper (T H ) 1 and T H 17 polarization of effector T cells (3, 4), and by promoting B-cell activation and terminal differentiation to antibody-secreting plasma cells (5, 6).Following infection or vaccination, antibody responses generally proceed in two phases: an initial extrafollicular response, which rapidly generates short-lived plasmablasts that secrete low-affinity IgM and small quantities of isotype-switched antibodies (7), and a slower germinal center (GC) response, where B cells switch Ig isotype, increase affinity for antigen through somatic mutation of IgH and IgL genes, and undergo selection processes (8). Importantly, the GC builds protection from reinfection by selecting long-lived plasma cells and memory B cells from cells expressing isotype-switched, affinity-matured Bcell antigen receptors (BCRs) (9). Initially, it was proposed that TLR signaling selectively favored the extrafollicular component of serological immunity (10), but it was shown subsequently that TLR signaling in B cells could greatly augment the GC response to virus-like particles, nanoparticles, and virions (5,11,12). Moreover, the ability of B-cell TLRs to enhance the antibody response was recently shown to be important for host defense of mice infected with Friend virus and the chronic version of lymphocytic choriomeningitis virus (LCMV) (12)(13)(14).Follicular helper T (T FH ) cells maintain the GC and govern selection for GC B cells with increased affinity for antigen (...

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“…Villin-Cre transgenic mice were crossed to Myd88 f/f mice (a generous gift from Dr Anthony DeFranco, UCSF, CA), which contain loxP sites flanking exon 3 to generate mice lacking exon 3 of Myd88 gene in IECs (Myd88 IEC−/− ). 16 Tail snips were collected from all pups generated from crosses, and genomic DNA was isolated using a Qiagen Blood and Tissue Kit (Qiagen; Valencia, CA). Primers used for genotyping were as followed: Villin-Cre promoter (5'-GCGGTCTGGCAGTAAAAACTATC-3', and 5'-GTGAAACAGCATTGCTGTCACTT-3') and MyD88 f/f (5'-GTTGTGTGTGTCCGACCGT-3' and 5'-GTCAGAAACAACCACCACCATGC-3').…”

Section: Generation Of Myd88 Iec−/− Micementioning

confidence: 99%

324 Epithelial Cell Specific MyD88 Signaling Mediates Ischemia/Reperfusion-Induced Intestinal Injury Independent of Microbial Status

Muehlbauer¹,

Perez‐Chanona²,

Jobin³

2012

Gastroenterology

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Toll-like Receptors Activate Innate and Adaptive Immunity by using Dendritic Cell-Intrinsic and -Extrinsic Mechanisms

Cited by 329 publications

References 38 publications

γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface

γδ intraepithelial lymphocytes are essential mediators of host–microbial homeostasis at the intestinal mucosal surface

Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses

324 Epithelial Cell Specific MyD88 Signaling Mediates Ischemia/Reperfusion-Induced Intestinal Injury Independent of Microbial Status

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