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Dive into the research topics where Kevin M. Dennehy is active.

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Featured researches published by Kevin M. Dennehy.


Nature Immunology | 2007

Dectin-1 is required for beta-glucan recognition and control of fungal infection.

Philip R. Taylor; S. Vicky Tsoni; Janet A. Willment; Kevin M. Dennehy; Marcela Rosas; Helen Findon; Ken Haynes; Chad Steele; Marina Botto; Siamon Gordon; Gordon D. Brown

β-Glucan is one of the most abundant polysaccharides in fungal pathogens, yet its importance in antifungal immunity is unclear. Here we show that deficiency of dectin-1, the myeloid receptor for β-glucan, rendered mice susceptible to infection with Candida albicans. Dectin-1-deficient leukocytes demonstrated significantly impaired responses to fungi even in the presence of opsonins. Impaired leukocyte responses were manifested in vivo by reduced inflammatory cell recruitment after fungal infection, resulting in substantially increased fungal burdens and enhanced fungal dissemination. Our results establish a fundamental function for β-glucan recognition by dectin-1 in antifungal immunity and demonstrate a signaling non–Toll-like pattern-recognition receptor required for the induction of protective immune responses.


European Journal of Immunology | 2008

Syk kinase is required for collaborative cytokine production induced through Dectin-1 and Toll-like receptors

Kevin M. Dennehy; Gerben Ferwerda; Inês Faro-Trindade; Elwira Pyż; Janet A. Willment; Philip R. Taylor; Ann M. Kerrigan; S. Vicky Tsoni; Siamon Gordon; Friederike Meyer-Wentrup; Gosse J. Adema; Bart Jan Kullberg; Edina Schweighoffer; Victor L. J. Tybulewicz; Héctor M. Mora-Montes; Neil A. R. Gow; David L. Williams; Mihai G. Netea; Gordon D. Brown

Recognition of microbial components by germ‐line encoded pattern recognition receptors (PRR) initiates immune responses to infectious agents. We and others have proposed that pairs or sets of PRR mediate host immunity. One such pair comprises the fungal β‐glucan receptor, Dectin‐1, which collaborates through an undefined mechanism with Toll‐like receptor 2 (TLR2) to induce optimal cytokine responses in macrophages. We show here that Dectin‐1 signaling through the spleen tyrosine kinase (Syk) pathway is required for this collaboration, which can also occur with TLR4, 5, 7 and 9. Deficiency of either Syk or the TLR adaptor MyD88 abolished collaborative responses, which include TNF, MIP‐1α and MIP‐2 production, and which are comparable to the previously described synergy between TLR2 and TLR4. Collaboration of the Syk and TLR/MyD88 pathways results in sustained degradation of the inhibitor of kB (IkB), enhancing NFkB nuclear translocation. These findings establish the first example of Syk‐ and MyD88‐coupled PRR collaboration, further supporting the concept that paired receptors collaborate to control infectious agents.


Journal of Biological Chemistry | 2008

CLEC9A is a novel activation C-type lectin-like receptor expressed on BDCA3+ dendritic cells and a subset of monocytes.

Cristal Huysamen; Janet A. Willment; Kevin M. Dennehy; Gordon D. Brown

We describe here the first characterization of CLEC9A, a group V C-type lectin-like receptor located in the “Dectin-1 cluster” of related receptors, which are encoded within the natural killer (NK)-gene complex. Expression of human CLEC9A is highly restricted in peripheral blood, being detected only on BDCA3+ dendritic cells and on a small subset of CD14+CD16- monocytes. CLEC9A is expressed at the cell surface as a glycosylated dimer and can mediate endocytosis, but not phagocytosis. CLEC9A possesses a cytoplasmic immunoreceptor tyrosine-based activation-like motif that can recruit Syk kinase, and we demonstrate, using receptor chimeras, that this receptor can induce proinflammatory cytokine production. These data indicate that CLEC9A functions as an activation receptor.


Journal of Experimental Medicine | 2003

Topological Requirements and Signaling Properties of T Cell–activating, Anti-CD28 Antibody Superagonists

Fred Lühder; Yun Huang; Kevin M. Dennehy; Christine Guntermann; Ingrid Müller; Erna Winkler; Thomas Kerkau; Shinji Ikemizu; Simon J. Davis; Thomas Hanke; Thomas Hünig

Full activation of naive T cells requires both engagement of the T cell antigen receptor (TCR; signal 1) and costimulatory signaling by CD28 (signal 2). We previously identified two types of rat CD28-specific monoclonal antibodies (mAbs): “conventional,” TCR signaling–dependent costimulatory mAbs and “superagonistic” mAbs capable of inducing the full activation of primary resting T cells in the absence of TCR ligation both in vitro and in vivo. Using chimeric rat/mouse CD28 molecules, we show that the superagonists bind exclusively to the laterally exposed C′′D loop of the immunoglobulin-like domain of CD28 whereas conventional, costimulatory mAbs recognize an epitope close to the binding site for the natural CD80/CD86 ligands. Unexpectedly, the C′′D loop reactivity of a panel of new antibodies raised against human CD28 could be predicted solely on the basis of their superagonistic properties. Moreover, mouse CD28 molecules engineered to express the rat or human C′′D loop sequences activated T cell hybridomas without TCR ligation when cross-linked by superagonistic mAbs. Finally, biochemical analysis revealed that superagonistic CD28 signaling activates the nuclear factor κB pathway without inducing phosphorylation of either TCRζ or ZAP70. Our findings indicate that the topologically constrained interactions of anti-CD28 superagonists bypass the requirement for signal 1 in T cell activation. Antibodies with this property may prove useful for the development of T cell stimulatory drugs.


Journal of Leukocyte Biology | 2007

The role of the β-glucan receptor Dectin-1 in control of fungal infection

Kevin M. Dennehy; Gordon D. Brown

During fungal infection, a variety of receptors initiates immune responses, including TLR and the β‐glucan receptor Dectin‐1. TLR recognition of fungal ligands and subsequent signaling through the MyD88 pathway were thought to be the most important interactions required for the control of fungal infection. However, recent papers have challenged this view, highlighting the role of Dectin‐1 in induction of cytokine responses and the respiratory burst. Two papers, using independently derived, Dectin‐1‐deficient mice, address the role of Dectin‐1 in control of fungal infection. Saijo et al. [ 1 ] argue that Dectin‐1 plays a minor role in control of Pneumocystis carinii by direct killing and that TLR‐mediated cytokine production controls P. carinii and Candida albicans. By contrast, Taylor et al. [ 2 ] argue that Dectin‐1‐mediated cytokine and chemokine production, leading to efficient recruitment of inflammatory cells, is required for control of fungal infection. In this review, we argue that collaborative responses induced during infection may partially explain these apparently contradictory results. We propose that Dectin‐1 is the first of many pattern recognition receptors that can mediate their own signaling, as well as synergize with TLR to initiate specific responses to infectious agents.


European Journal of Immunology | 2009

Reciprocal regulation of IL-23 and IL-12 following co-activation of Dectin-1 and TLR signaling pathways

Kevin M. Dennehy; Janet A. Willment; David L. Williams; Gordon D. Brown

Recognition of microbial products by germ‐line‐encoded PRR initiates immune responses, but how PRR mediate specific host responses to infectious agents is poorly understood. We and others have proposed that specificity is achieved by collaborative responses mediated between different PRR. One such example comprises the fungal β‐glucan receptor Dectin‐1, which collaborates with TLR to induce TNF production. We show here that collaborative responses mediated by Dectin‐1 and TLR2 are more extensive than first appreciated, and result in enhanced IL‐23, IL‐6 and IL‐10 production in DC, while down‐regulating IL‐12 relative to the levels produced by TLR ligation alone. Such down‐regulation occurred with multiple MyD88‐coupled TLR, was dependent on signaling through Dectin‐1 and also occurred in macrophages. These findings explain how fungi can induce IL‐23 and IL‐6, while suppressing IL‐12, a combination which has previously been shown to contribute to the development of Th17 responses found during fungal infections. Furthermore, these data reveal how the collaboration of different PRR can tailor specific responses to infectious agents.


Journal of Immunology | 2009

CLEC-2 is a phagocytic activation receptor expressed on murine peripheral blood neutrophils

Ann M. Kerrigan; Kevin M. Dennehy; Diego Mourão-Sá; Inês Faro-Trindade; Janet A. Willment; Philip R. Taylor; Johannes A. Eble; Caetano Reis e Sousa; Gordon D. Brown

CLEC-2 is a member of the “dectin-1 cluster” of C-type lectin-like receptors and was originally thought to be restricted to platelets. In this study, we demonstrate that murine CLEC-2 is also expressed by peripheral blood neutrophils, but only weakly by bone marrow or elicited inflammatory neutrophils. On circulating neutrophils, CLEC-2 can mediate phagocytosis of Ab-coated beads and the production of proinflammatory cytokines, including TNF-α, in response to the CLEC-2 ligand, rhodocytin. CLEC-2 possesses a tyrosine-based cytoplasmic motif similar to that of dectin-1, and we show using chimeric analyses that the activities of this receptor are dependent on this tyrosine. Like dectin-1, CLEC-2 can recruit the signaling kinase Syk in myeloid cells, however, stimulation of this pathway does not induce the respiratory burst. These data therefore demonstrate that CLEC-2 expression is not restricted to platelets and that it functions as an activation receptor on neutrophils.


Journal of Biological Chemistry | 2012

The C-type Lectin Receptor CLECSF8 (CLEC4D) Is Expressed by Myeloid Cells and Triggers Cellular Activation through Syk Kinase

Lisa M. Graham; Vandana Gupta; Georgia Schäfer; Delyth M. Reid; Matti Kimberg; Kevin M. Dennehy; William G. Hornsell; Reto Guler; Maria A. Campanero-Rhodes; Angelina S. Palma; Ten Feizi; Stella K. Kim; Peter Sobieszczuk; Janet A. Willment; Gordon D. Brown

Background: C-type lectins play important roles in immunity and homeostasis. Results: CLECSF8 is expressed on neutrophils and monocytes and can mediate phagocytosis, the respiratory burst and inflammatory cytokine production, in part through association with a novel adaptor. Conclusion: CLECSF8 can trigger cellular activation. Significance: This study identifies a novel C-type lectin that can control immune cell function. CLECSF8 is a poorly characterized member of the “Dectin-2 cluster” of C-type lectin receptors and was originally thought to be expressed exclusively by macrophages. We show here that CLECSF8 is primarily expressed by peripheral blood neutrophils and monocytes and weakly by several subsets of peripheral blood dendritic cells. However, expression of this receptor is lost upon in vitro differentiation of monocytes into dendritic cells or macrophages. Like the other members of the Dectin-2 family, which require association of their transmembrane domains with signaling adaptors for surface expression, CLECSF8 is retained intracellularly when expressed in non-myeloid cells. However, we demonstrate that CLECSF8 does not associate with any known signaling adaptor molecule, including DAP10, DAP12, or the FcRγ chain, and we found that the C-type lectin domain of CLECSF8 was responsible for its intracellular retention. Although CLECSF8 does not contain a signaling motif in its cytoplasmic domain, we show that this receptor is capable of inducing signaling via Syk kinase in myeloid cells and that it can induce phagocytosis, proinflammatory cytokine production, and the respiratory burst. These data therefore indicate that CLECSF8 functions as an activation receptor on myeloid cells and associates with a novel adaptor molecule. Characterization of the CLECSF8-deficient mice and screening for ligands using oligosaccharide microarrays did not provide further insights into the physiological function of this receptor.


PLOS ONE | 2009

Rapid Regulatory T-Cell Response Prevents Cytokine Storm in CD28 Superagonist Treated Mice

Tea Gogishvili; Daniela Langenhorst; Fred Lühder; Fernando Elias; Karin Elflein; Kevin M. Dennehy; Ralf Gold; Thomas Hünig

Superagonistic CD28-specific monoclonal antibodies (CD28SA) are highly effective activators of regulatory T-cells (Treg cells) in rats, but a first-in-man trial of the human CD28SA TGN1412 resulted in an unexpected cytokine release syndrome. Using a novel mouse anti-mouse CD28SA, we re-investigate the relationship between Treg activation and systemic cytokine release. Treg activation by CD28SA was highly efficient but depended on paracrine IL-2 from CD28SA-stimulated conventional T-cells. Systemic cytokine levels were innocuous, but depletion of Treg cells prior to CD28SA stimulation led to systemic release of proinflammatory cytokines, indicating that in rodents, Treg cells effectively suppress the inflammatory response. Since the human volunteers of the TGN1412 study were not protected by this mechanism, we also tested whether corticosteroid prophylaxis would be compatible with CD28SA induced Treg activation. We show that neither the expansion nor the functional activation of Treg cells is affected by high-dose dexamethasone sufficient to control systemic cytokine release. Our findings warn that preclinical testing of activating biologicals in rodents may miss cytokine release syndromes due to the rapid and efficacious response of the rodent Treg compartment, and suggest that polyclonal Treg activation is feasible in the presence of antiphlogistic corticosteroid prophylaxis.


Journal of Immunology | 2006

Cutting Edge: Monovalency of CD28 Maintains the Antigen Dependence of T Cell Costimulatory Responses

Kevin M. Dennehy; Fernando Elias; Gabrielle Zeder-Lutz; Xin Ding; Danièle Altschuh; Fred Lühder; Thomas Hünig

CD28 and CTLA-4 are the major costimulatory receptors on naive T cells. But it is not clear why CD28 is monovalent whereas CTLA-4 is bivalent for their shared ligands CD80/86. We generated bivalent CD28 constructs by fusing the extracellular domains of CTLA-4 or CD80 with the intracellular domains of CD28. Bivalent or monovalent CD28 constructs were ligated with recombinant ligands with or without TCR coligation. Monovalent CD28 ligation did not induce responses unless the TCR was coligated. By contrast, bivalent CD28 ligation induced responses in the absence of TCR engagement. To extend these findings to primary cells, we used novel superagonistic and conventional CD28 Abs. Superagonistic Ab D665, but not conventional Ab E18, predominantly ligates CD28 bivalently at low CD28/Ab ratios and induces Ag-independent T cell proliferation. Monovalency of CD28 for its natural ligands is thus essential to provide costimulation without inducing responses in the absence of TCR engagement.

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Fred Lühder

University of Göttingen

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Gerhard Jahn

Boston Children's Hospital

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Gregor Blank

University of Würzburg

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