Antigen-specific Vγ2Vδ2 T effector cells confer homeostatic protection against pneumonic plaque lesions

Huang, Dan; Chen, Crystal Y.; Ali, Zahida; Shao, Lingyun; Shen, Lei; Lockman, Hank; Barnewall, Roy E.; Sabourin, Carol L.; Eestep, James; Reichenberg, Armin; Hintz, Martin; Jomaa, Hassan; Wang, Thomas J.; Chen, Zheng W.

doi:10.1073/pnas.0811250106

Cited by 40 publications

(60 citation statements)

References 29 publications

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“…39) and functional defects within V␥9V␦2 T cells in patients chronically infected by HIV and hepatitis C virus (40,41). Owing to expression of CCR5 and CXCR3, peripheral effector V␥9V␦2 T cells are likely to be recruited to inflamed tissues during early stages of microbial infections (42,43,44,45). Therefore, following contact with shortterm pathogen-associated molecular patterns-sensitized iDC and pDC, infiltrating effector ␥␦ T cells might contribute to the local innate immune response by rapidly secreting high amounts of IFN-␥ and thus play a role in the containment of invading pathogens.…”

Section: Discussionmentioning

confidence: 99%

Early Triggering of Exclusive IFN-γ Responses of Human Vγ9Vδ2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells

Devilder

Allain-Maillet

Dousset

et al. 2009

The Journal of Immunology

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γδ T cells, a major innate-like T cell subset, are thought to play in vivo an important role in innate and adaptive immune responses to various infection agents like parasites, bacteria, or viruses but the mechanisms contributing to this immune process remain ill defined. Owing to their ability to recognize a broad set of microbial molecular patterns, TLRs represent a major innate pathway through which pathogens induce dendritic cells (DC) maturation and acquisition of immunostimulatory functions. In this study, we studied the effects of various TLR ligands on the activation of human Vγ9Vδ2 T cells, a main human γδ PBL subset, which has been recently involved in the licensing of mycobacteria-infected DC. Both TLR3 and TLR4, but not TLR2 ligands, induced a rapid, strong, and exclusive IFN-γ production by Vγ9Vδ2 T cells. This γδ subset contributed to a large extent to the overall PBL IFN-γ response induced after short-term TLR stimulation of human PBMC. Importantly, this phenomenon primarily depended on type I IFN, but not IL-12, produced by monocytic DC upon TLR engagement. Vγ9Vδ2 T cells were similarly activated by plasmacytoid DC upon TLR8/9 activation or Yellow Fever virus infection. Moreover TLR-induced Vγ9Vδ2 IFN-γ noncytolytic response led to efficient DC polarization into IL-12p70-producing cells. Our results support an adjuvant role played by Vγ9Vδ2 T cells along microbial infections through a particular cross-talk with pathogen-associated molecular patterns-activated DC. Moreover they provide new insights into the mechanisms underlying functional activation of this unique peripheral innate-like T cell subset during viral infections.

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Section: Discussionmentioning

confidence: 99%

Early Triggering of Exclusive IFN-γ Responses of Human Vγ9Vδ2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells

Devilder

Allain-Maillet

Dousset

et al. 2009

The Journal of Immunology

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“…The contribution of V␥2V␦2 T cells to anti-MPV immunity cannot be ruled out, although neutralizing antibodies are sufficient for vaccinia virus-induced immunity to monkeypox (9). The capability of ␥␦ T cells to localize in inflamed lung tissues in monkeypox also suggests that V␥2V␦2 T cells may play a role in homeostatic protection against lung lesions in monkeypox, as they do in bacterial infection (13).…”

Section: V␥2v␦2 T Cells Could Share Some Immune Kinetics With Virus-smentioning

confidence: 99%

Expansion, Reexpansion, and Recall-Like Expansion of Vγ2Vδ2 T Cells in Smallpox Vaccination and Monkeypox Virus Infection

Shao

Huang

Wei

et al. 2009

J Virol

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Little is known about the in vivo kinetics of T-cell responses in smallpox/monkeypox. We showed that macaque V␥2V␦2 T cells underwent 3-week-long expansion after smallpox vaccine immunization and displayed simple reexpansion in association with sterile anti-monkeypox virus (anti-MPV) immunity after MPV challenge. Virus-activated V␥2V␦2 T cells exhibited gamma interferon-producing effector function after phosphoantigen stimulation. Surprisingly, like ␣␤ T cells, suboptimally primed V␥2V␦2 T cells in vaccinia virus/cidofovir-covaccinated macaques mounted major recall-like expansion after MPV challenge. Finally, V␥2V␦2 T cells localized in inflamed lung tissues for potential regulation. Our studies provide the first in vivo evidence that viruses, despite their inability to produce exogenous phosphoantigen, can induce expansion, reexpansion, and recall-like expansion of V␥2V␦2 T cells and stimulate their antimicrobial cytokine response.Human ␥␦ T cells appear to contribute to both innate and adaptive immune responses (4,6,10,19). V␥2V␦2 T cells exist only in primates, and in humans, they constitute 60 to 95% of total blood ␥␦ T cells. The capacity of V␥2V␦2 T cells to undergo major clonal expansion in primary infection and to mount rapid recall expansion upon reinfection has been proposed as an adaptive immune response (6), which is consistent with memory phenotypes of V␥2V␦2 T cells (7), long-term expansion of memory-like V␦2 T cells, and in vitro recall expansion of blood ␥␦ T cells in vaccinated or infected humans (1, 15a, 16, 17, 25). It is important to note that the microbial antigen recognized by V␥2V␦2 T cells is temporally limited to (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), commonly referred to as phosphoantigen, produced in the newly discovered 2-C-methyl-D-erythritol-4-phosphate pathway of isoprenoid biosynthesis in bacteria, but not viruses (8).Our recent study has demonstrated that HMBPP is presented by a putative molecule on antigen-presenting cell membranes and recognized by V␥2V␦2 T-cell receptor (TCR) (24). Since viruses do not produce exogenous HMBPP recognized by V␥2V␦2 T cells, in vivo V␥2V␦2 T-cell expansion usually occurs only in HMBPP-producing bacterial or protozoal infections.Monkeypox virus (MPV) (an orthopoxvirus) has biological features similar to those of smallpox virus, and MPV infection is clinically similar to smallpox in humans (9,12,22). Immune responses of V␥2V␦2 T cells during lethal MPV infection have not been studied, although some laboratories have undertaken in vitro studies of ␥␦ T-cell immune responses to vaccinia virus (1, 2, 15). We presume that initial vaccinia virus immunization and subsequent MPV challenge of macaques would provide an ideal in vivo setting in which to determine whether V␥2V␦2 T cells can mount innate-like or recall-like responses to orthopoxvirus infections. We made a novel observation indicating expansion, reexpansion, and recall-like expansion of V␥2V␦2 T cells with effector function in response to smallpox vaccination and MPV infection...

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“…The OCT tissue blocks were cut into 6-m sections using a cryostat, as previously described (26). The frozen tissue sections were fixed with cold acetone for 10 min, rinsed with PBS, and then blocked with protein-blocking serum-free buffer .…”

Section: Methodsmentioning

confidence: 99%

Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection Leading to Paralytic Poliomyelitis

Shen

Chen

Huang

et al. 2017

J Virol

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Despite a great deal of prior research, the early pathogenic events in natural oral poliovirus infection remain poorly defined. To establish a model for study, we infected 39 macaques by feeding them single high doses of the virulent Mahoney strain of wild type 1 poliovirus. Doses ranging from 10 7 to 10 9 50% tissue culture infective doses (TCID 50 ) consistently infected all the animals, and many monkeys receiving 10 8 or 10 9 TCID 50 developed paralysis. There was no apparent difference in the susceptibilities of the three macaque species (rhesus, cynomolgus, and bonnet) used. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia, and virus was isolated from tonsils, gut mucosa, and draining lymph nodes. Viral replication proteins were detected in both epithelial and lymphoid cell populations expressing CD155 in the tonsil and intestine, as well as in spinal cord neurons. Necrosis was observed in these three cell types, and viral replication in the tonsil/gut was associated with histopathologic destruction and inflammation. The sustained response of neutralizing antibody correlated temporally with resolution of viremia and termination of virus shedding in oropharynges and feces. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract) and lymphoid/monocytic cells in tonsils and Peyer's patches (explaining viremia), extending previous studies of poliovirus pathogenesis in humans. Because the model recapitulates human poliovirus infection and poliomyelitis, it can be used to study polio pathogenesis and to assess the efficacy of candidate antiviral drugs and new vaccines.IMPORTANCE Early pathogenic events of poliovirus infection remain largely undefined, and there is a lack of animal models mimicking natural oral human infection leading to paralytic poliomyelitis. All 39 macaques fed with single high doses ranging from 10 7 to 10 9 TCID 50 Mahoney type 1 virus were infected, and many of the monkeys developed paralysis. Virus excretion in stool and nasopharynges was consistently observed, with occasional viremia; tonsil, mesentery lymph nodes, and intestinal mucosa served as major target sites of viral replication. For the first time, this model demonstrates that early in the infectious process, poliovirus replication occurs in both epithelial cells (explaining virus shedding in the gastrointestinal tract)

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Antigen-specific Vγ2Vδ2 T effector cells confer homeostatic protection against pneumonic plaque lesions

Abstract: (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate immunotherapeutics ͉ lung ͉ macaques ͉ immune regulation ͉ clonal expansion

Cited by 40 publications

References 29 publications

Early Triggering of Exclusive IFN-γ Responses of Human Vγ9Vδ2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells

Early Triggering of Exclusive IFN-γ Responses of Human Vγ9Vδ2 T Cells by TLR-Activated Myeloid and Plasmacytoid Dendritic Cells

Expansion, Reexpansion, and Recall-Like Expansion of Vγ2Vδ2 T Cells in Smallpox Vaccination and Monkeypox Virus Infection

Pathogenic Events in a Nonhuman Primate Model of Oral Poliovirus Infection Leading to Paralytic Poliomyelitis

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