DAP12 Signaling Directly Augments Proproliferative Cytokine Stimulation of NK Cells during Viral Infections

Self Cite

Transmembrane signaling adaptor DAP12 has increasingly been recognized for its important role in innate responses. However, its role in the regulation of antimicrobial T cell responses has remained unknown. In our current study, we have examined host defense, T cell responses, and tissue immunopathology in models of intracellular infection established in wild-type and DAP12-deficient mice. During mycobacterial infection, lack of DAP12 leads to pronounced proinflammatory and Th1 cytokine responses, overactivation of Ag-specific CD4 and CD8 T cells of type 1 phenotype, and heightened immunopathology both in the lung and lymphoid organs. DAP12-deficient airway APC display enhanced NF-κB activation and cytokine responses upon TLR stimulation or mycobacterial infection in vitro. Of importance, adoptive transfer of Ag-loaded DAP12-deficient APC alone could lead to overactivation of transferred transgenic or endogenous wild-type T cells in vivo. We have further found that the immune regulatory role by DAP12 is not restricted only to intracellular bacterial infection, since lack of this molecule also leads to uncontrolled type 1 T cell activation and severe immunopathology and tissue injury during intracellular viral infection. Our study thus identifies DAP12 as an important novel immune regulatory molecule that acts, via APC, to control the level of antimicrobial type 1 T cell activation and immunopathology.

Section: Discussionsupporting

confidence: 61%

mentioning

confidence: 99%

Critical Negative Regulation of Type 1 T Cell Immunity and Immunopathology by Signaling Adaptor DAP12 during Intracellular Infection

Divangahi

Yang

Kugathasan

et al. 2007

Self Cite

“…Additional candidates that could contribute to the MyD88-dependent resistance to MCMV infection include IL-18 and IL-1. A role of IL-18 is unlikely, because IL-18 Ϫ/Ϫ animals are as resistant as WT controls (19,21). In contrast, a role of IL-1 cannot be formally excluded, although IL-1R Ϫ/Ϫ animals harbor normal pDC functions and systemic levels of IL-12, IFN-␣, and TNF-␣ (data not shown).…”

Section: Discussionmentioning

confidence: 93%

Cutting Edge: Overlapping Functions of TLR7 and TLR9 for Innate Defense against a Herpesvirus Infection

Zucchini

Bessou

Traub

et al. 2008

118

127

As initially demonstrated with murine cytomegalovirus (MCMV), plasmacytoid dendritic cells (pDCs) are the major source of IFN-α/β in response to a variety of viruses in vivo. However, contradictory results have been obtained pertaining to the mechanisms promoting IFN-α/β production by pDCs in response to MCMV. In this study we show that TLR7 and TLR9 exert redundant functions for IFN-α/β, IL-12p40, and TNF-α production by pDCs in vivo during MCMV infection. In contrast, we confirm that systemic production of IL-12p70 strictly depends on TLR9. The combined loss of TLR7 and TLR9 recapitulates critical features of the phenotype of MyD88-deficient mice, including a dramatic decrease in systemic IFN-α/β levels, an increase in viral load, and increased susceptibility to MCMV-induced mortality. This is the first demonstration of the implication of TLR7 in the recognition of a DNA virus.

“…The novel findings from our current study together with the previous reports suggest an emerging paradigm that the functional outcome of DAP12 signaling pathway is largely defined by the nature of Ags or infectious agents and that the conclusion derived from mere in vitro studies can be misleading. Thus, the role of DAP12 pathway may be proimmune when the host is exposed in vivo to inert Ags (39) or extracellular infectious agents or isolated pattern recognition receptor ligands (31,37,58). However, when the host is exposed to the intact intracellular infectious agents such as murine cytomegalovirus (35), Listeria monocytogene (34), Mycobacterium bovis (36), or influenza A virus (current study), DAP12 plays a critical immune suppressive role.…”

Section: Discussionmentioning

confidence: 99%

“…A number of innate immune receptors including the triggering receptor expressed on myeloid cells, MDL-1 and NKG2D, are associated with and signal though DAP12 (24)(25)(26)(27)(28)(29). Although initially identified to be a proinflammatory or immune-activating molecule, recent emerging evidence suggests a dual role of DAP12 signaling pathway, depending on the target immune cell type, the nature of Ags or infectious agents or the variation in different animal models (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40). However, the precise role of DAP12 pathway in the regulation of immunopathogenic T cell subsets and immunopathology in acute influenza infection remains unclear.…”

Section: †mentioning

confidence: 99%

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

McCormick

Shaler

Small

et al. 2011

Immunopathology is a major cause of influenza-associated morbidity and mortality worldwide. However, the role and regulatory mechanisms of CD4 T cells in severe lung immunopathology following acute influenza infection are poorly understood. In this paper, we report that the emergence of immunopathogenic CD4 T cells is under the control of a transmembrane immunoadaptor DAP12 pathway during influenza infection. We find that the mice lacking DAP12 have unaltered viral clearance but easily succumb to influenza infection as a result of uncontrolled immunopathology. Such immunopathology is associated with markedly increased CD4 T cells displaying markedly increased cytotoxicity and Fas ligand expression. Furthermore, the immunopathogenic property of these CD4 T cells is transferrable. Thus, depletion of CD4 T cells or abrogation of Fas/Fas ligand signaling pathway improves survival and immunopathology. We further find that DAP12 expressed by dendritic cells plays an important role in controlling the immunopathogenic CD4 T cells during influenza infection. Our findings identify a novel pathway that controls the level of immune-pathogenic CD4 T cells during acute influenza infection.