Control of Pathogenic CD4 T Cells and Lethal Immunopathology by Signaling Immunoadaptor DAP12 during Influenza Infection

McCormick, Sarah; Shaler, Christopher R.; Small, Cherrie; Horvath, Carly; Damjanovic, Daniela; Brown, Earl G.; Aoki, Naoko; Takai, Toshiyuki; Xing, Zhou

doi:10.4049/jimmunol.1101050

Cited by 16 publications

(10 citation statements)

References 61 publications

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“…The present study expands current knowledge of the involvement of DAP12 in host defense against intracellular microorganisms (12,15,38) and influenza virus (33,38), showing for the first time that DAP12 impairs host defense during respiratory tract infection caused by S. pneumoniae. Our studies were limited to one pneumococcal strain.…”

Section: Discussionsupporting

confidence: 70%

“…In a colitis model induced by streptomycin administration and oral infection with Salmonella Typhimurium, dap12 -/mice had higher bacterial burdens in their ceca than Wt mice, which was associated with increased local inflammation (15). In this respect, it should be noted that the lung is of particular interest for studies on DAP12 and antibacterial defense, considering its constitutive expression in this organ (32,33). Although this study (15) hinted at a role for DAP12 in antibacterial defense, at least in the intestine, dap12 -/mice displayed reduced bacterial loads after IV infection with the intracellular bacterium L. monocytogenes (12).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DNAX-Activating Protein of 12 kDa Impairs Host Defense in Pneumococcal Pneumonia

Hommes

Hoogendijk

Dessing

et al. 2014

Critical Care Medicine

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

DNAX-Activating Protein of 12 kDa Impairs Host Defense in Pneumococcal Pneumonia

Hommes

Hoogendijk

Dessing

et al. 2014

Critical Care Medicine

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“…In this work, we have discovered that DAP12 signaling following C. neoformans challenge contributes to an immune response that is detrimental to the host. Although other studies have demonstrated that DAP12 can be either beneficial or detrimental depending on the microbial and tissue context (22)(23)(24)(25)(26)(27)(28), this study represents the first evidence that DAP12 signaling can be unfavorable to the host during a fungal infection. The downstream effects of this DAP12-mediated pathway appear to be 3-fold: increased pulmonary eosinophilia and suppression of the antifungal activity of both NK cells and macrophages.…”

Section: Discussionmentioning

confidence: 92%

DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans

Heung

Hohl

2016

Infect Immun

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Cryptococcus neoformans is an opportunistic fungal pathogen that is inhaled into the lungs and can lead to life-threatening meningoencephalitis in immunocompromised patients. Currently, the molecular mechanisms that regulate the mammalian immune response to respiratory cryptococcal challenge remain poorly defined. DAP12, a signaling adapter for multiple pattern recognition receptors in myeloid and natural killer (NK) cells, has been shown to play both activating and inhibitory roles during lung infections by different bacteria and fungi. In this study, we demonstrate that DAP12 plays an important inhibitory role in the immune response to C. neoformans. Infectious outcomes in DAP12 ؊/؊ mice, including survival and lung fungal burden, are significantly improved compared to those in C57BL/6 wild-type (WT) mice. We find that eosinophils and macrophages are decreased while NK cells are increased in the lungs of infected DAP12 ؊/؊ mice. In contrast to WT NK cells, DAP12 ؊/؊ NK cells are able to repress C. neoformans growth in vitro. Additionally, DAP12؊/؊ macrophages are more highly activated than WT macrophages, with increased production of tumor necrosis factor (TNF) and CCL5/RANTES and more efficient uptake and killing of C. neoformans. These findings suggest that DAP12 acts as a brake on the pulmonary immune response to C. neoformans by promoting pulmonary eosinophilia and by inhibiting the activation and antifungal activities of effector cells, including NK cells and macrophages.T he environmental encapsulated yeast Cryptococcus neoformans is a common cause of invasive fungal infections in immunocompromised patients, including those with AIDS, solid organ transplants, and hematologic malignancies (1). When C. neoformans cells are inhaled into the lung, healthy individuals typically clear the infectious particles in an asymptomatic manner. However, in immunocompromised hosts, C. neoformans can proliferate in the lung, disseminate to the brain, and cause meningoencephalitis. Despite contemporary combination antifungal therapy, the survival rate for disseminated cryptococcosis approaches only 70% (2). Furthermore, the at-risk population for cryptococcosis is expanding due to the development and increased availability of novel immunosuppressive regimens for autoimmunity, transplantation, and cancer.An important approach to developing more efficacious therapies for cryptococcosis is to decipher the initial immune response in the lung that regulates fungal proliferation and tissue invasion. Classically, host defenses are triggered when fungal pathogen-associated molecular patterns (PAMPs) are detected by immune cell pattern recognition receptors (PRRs), such as C-type lectin receptors (CLRs) or Toll-like receptors (TLRs). Studies on the intracellular signaling molecules CARD9 (3) and MyD88 (4-6), which can mediate events downstream of CLRs and TLRs or interleukin-1 receptor superfamily members, respectively, suggest that these pathways play a role in mounting an effective immune response to C. neoformans. However, so f...

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“…Thus, DC-ITAM modulation of TLR, GM-CSF or IFNAR signaling pathways might selectively alter external signals regulating inflammatory effector responses [9]. For example, Dap12 deficiency in mice results in altered activity of antigen-specific T cells [10]–[12]. Moreover, Dap12 and FcRγ deficiency results in complete protection against induction of experimental autoimmune encephalomyelitis (EAE) [8].…”

Section: Introductionmentioning

confidence: 99%

Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs

et al. 2013

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Dap12 and FcRγ, the two transmembrane ITAM-containing signaling adaptors expressed in dendritic cells (DC), are implicated in the regulation of DC function. Several activating and adhesion receptors including integrins require these chains for their function in triggering downstream signaling and effector pathways, however the exact role(s) for Dap12 and FcRγ remains elusive as their loss can lead to both attenuating and enhancing effects. Here, we report that mice congenitally lacking both Dap12 and FcRγ chains (DF) show a massively enhanced effector CD8+ T cell response to protein antigen immunization or West Nile Virus (WNV) infection. Thus, immunization of DF mice with MHCI-restricted OVA peptide leads to accumulation of IL-12-producing monocyte-derived dendritic cells (Mo-DC) in draining lymph nodes, followed by vastly enhanced generation of antigen-specific IFNγ-producing CD8+ T cells. Moreover, DF mice show increased viral clearance in the WNV infection model. Depletion of CCR2+ monocytes/macrophages in vivo by administration anti-CCR2 antibodies or clodronate liposomes completely prevents the exaggerated CD8+ T cell response in DF mice. Mechanistically, we show that the loss of Dap12 and FcRγ-mediated signals in Mo-DC leads to a disruption of GM-CSF receptor-induced STAT5 activation resulting in upregulation of expression of IRF8, a transcription factor. Consequently, Dap12- and FcRγ-deficiency exacerbates GM-CSF-driven monocyte differentiation and production of inflammatory Mo-DC. Our data suggest a novel cross-talk between DC-ITAM and GM-CSF signaling pathways, which controls Mo-DC differentiation, IL-12 production, and CD8+ T cell responses.

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Control of Pathogenic CD4 T Cells and Lethal Immunopathology by Signaling Immunoadaptor DAP12 during Influenza Infection

Cited by 16 publications

References 61 publications

DNAX-Activating Protein of 12 kDa Impairs Host Defense in Pneumococcal Pneumonia

DNAX-Activating Protein of 12 kDa Impairs Host Defense in Pneumococcal Pneumonia

DAP12 Inhibits Pulmonary Immune Responses to Cryptococcus neoformans

Loss of DAP12 and FcRγ Drives Exaggerated IL-12 Production and CD8+ T Cell Response by CCR2+ Mo-DCs

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