Innate immune response to encephalomyocarditis virus infection mediated by CD1d

Exley, Mark A.; Bigley, Nancy J.; Cheng, Olivia; Shaulov, Angela; Tahir, Syed Muhammad; Carter, Quincy L.; García, Jorge A.; Wang, Carren; Patten, Kurt; Stills, Harold F.; Alt, Frederick W.; Snapper, Scott B.; Balk, Steven P.

doi:10.1111/j.1365-2567.2003.01779.x

Cited by 73 publications

(101 citation statements)

References 67 publications

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“…(129 Â C57BL/6) F2 CD1d KO mice [50] were immunized i.p. and s.c. with invariant peptide-KLH and CFA, boosted 4-6 wk later with invariant peptide-BSA and IFA, and reboosted i.v.…”

Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

“…Imject TM -activated KLH, BSA, or OVA coupling was performed as recommended by the manufacturer (Pierce, Rockford, IL). (129 Â C57BL/6) F2 CD1d KO mice [50] were immunized i.p. and s.c. with invariant peptide-KLH and CFA, boosted 4-6 wk later with invariant peptide-BSA and IFA, and reboosted i.v.…”

Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

“…Thus, when the cyclic peptide was coupled to N-ethylmaleimide-activated KLH for immunization, BSA for boosting, and to OVA to screen hybridomas, the putative CDR3 loop would be exposed as an accessible epitope. Imject TM -activated KLH, BSA, or OVA coupling was performed as recommended by the manufacturer (Pierce, Rockford, IL).(129 Â C57BL/6) F2 CD1d KO mice [50] were immunized i.p. and s.c. with invariant peptide-KLH and CFA, boosted 4-6 wk later with invariant peptide-BSA and IFA, and reboosted i.v.…”

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Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

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A significant fraction of CD1d-restricted T cells express an invariant T cell receptor (TCR) a-chain. These highly conserved invariant NKT (iNKT) populations are important regulators of a wide spectrum of immune responses. The ability to directly identify and manipulate iNKT cells is essential to understanding their function and to exploit their therapeutic potential. To this end, we sought monoclonal and polyclonal antibodies specific for iNKT cells by immunizing CD1d KO mice, which lack iNKT cells, with a cyclic peptide modeled after the TCRa CDR3 loop. One mAb (6B11) was specific for cloned and primary human but not rodent iNKT cells and the human invariant TCRa, as shown by transfection and reactivity with human invariant TCRa transgenic T cells ex vivo and in situ. 6B11 was utilized to identify, purify, and expand iNKT cells from an otherwise minor component of human peripheral blood lymphocytes and to specifically identify human iNKT cells in tissue. Thus, we report a novel and general strategy for the generation of mAb specific for the CDR3 loop encoded by the TCR of interest. Specifically, an anti-Va24Ja18 CDR3 loop clonotypic TCR mAb is available for the enumeration and therapeutic manipulation of human and non-human primate iNKT populations.Key words: Anti-TCR Á Clonotypic Á Cyclic peptide Á IL-4 Á Invariant NKT Introduction Natural killer T (NKT) cells expressing surface markers found on NK cells (e.g. CD161, CD56, CD94 and/or KIR) comprise up to 20% of human peripheral blood lymphocytes (PBL) [1], whilst only *0.05% of PBL are CD1d restricted [2][3][4]. A major proportion of such PBL CD1d-reactive T cells are invariant NKT (iNKT) cells in that they express an invariant TCR a-chain, Va24Ja18 in humans and Va24Ja18 in mice [3,5,6]. Both human and murine iNKT cells can be activated in a CD1d-dependent fashion by the synthetic glycolipid a-galactosylceramide (a-GalCer) and self-or pathogen-derived glycolipid molecules [7][8][9]. Activation of iNKT cells leads to rapid production of large amounts of numerous cytokines and consequent stimulation of Mark A. Exley et al. Eur. J. Immunol. 2008. 38: 1756-1766 [3,[10][11][12][13][14], perhaps most significantly by regulating dendritic cell (DC) function [10,15]. The frequency and functional activity of iNKT cells have been shown to be important determinants for the progression of autoimmune disorders, tumors, and viral infections [10,[16][17][18]. In humans, a reduction in the number of circulating iNKT cells is accompanied by a striking Th1 polarization in certain autoimmune diseases such as type 1 diabetes, systemic sclerosis and rheumatoid arthritis [18][19][20][21]. Cancer patients have decreased numbers of iNKT cells in their blood and impaired in vitro proliferative potential, reversible with IL-2 [22][23][24]. As well as the reduced numbers of these cells found in many cancer patients, there is a striking reversal of cytokine polarization relative to that found in diabetes, which may reflect a reduction in iNKT anti-tumor activity during progression [...

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“…(129 Â C57BL/6) F2 CD1d KO mice [50] were immunized i.p. and s.c. with invariant peptide-KLH and CFA, boosted 4-6 wk later with invariant peptide-BSA and IFA, and reboosted i.v.…”

Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

Section: Isolation Of Invariant Tcr Cdr3 Loop-specific Antibodiesmentioning

confidence: 99%

mentioning

confidence: 99%

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Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Exley¹,

Hou²,

Shaulov³

et al. 2008

Eur J Immunol

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“…33,34 However, iNKT cells do not seem to participate in anti-viral immunity or control of viral replication during infection with encephalomyocarditis virus and murine cytomegalovirus. [35][36][37] The potential role of iNKT cells in experimental viral infections has also been studied using CD1d-deficient mice, which lack both iNKT cells and vNKT cells. Although it is not possible to differentiate between a role of iNKT cells, vNKT cells, or the CD1d molecule, comparison of CD1d-competent and CD1d-deficient mice has suggested that NKT cells might positively contribute to the immune response to infection with respiratory syncytial virus, Theiler's murine encephalomyelitis virus, encephalomyocarditis virus, and murine cytomegalovirus.…”

mentioning

confidence: 99%

“…Although it is not possible to differentiate between a role of iNKT cells, vNKT cells, or the CD1d molecule, comparison of CD1d-competent and CD1d-deficient mice has suggested that NKT cells might positively contribute to the immune response to infection with respiratory syncytial virus, Theiler's murine encephalomyelitis virus, encephalomyocarditis virus, and murine cytomegalovirus. 35,[37][38][39] Although there are relatively few iNKT cells in the human system, there is evidence for an antiviral role of these cells. 40 -43 Of note, the potential role of NKT cells during flavivirus infection has not yet been addressed.…”

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confidence: 99%

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

Renneson¹,

Guabiraba²,

Maillet³

et al. 2011

The American Journal of Pathology

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Dengue virus (DENV), a member of the mosquitoborne flaviviruses, is a serious public health problem in many tropical countries. We assessed the in vivo physiologic contribution of invariant natural killer T (iNKT) cells, a population of nonconventional lipidreactive ␣␤ T lymphocytes, to the host response during experimental DENV infection. We used a mouseadapted DENV serotype 2 strain that causes a disease that resembles severe dengue in humans. On DENV challenge, splenic and hepatic iNKT cells became activated insofar as CD69 and Fas ligand up-regulation and interferon-␥ production. C57BL/6 mice deficient in iNKT cells (J␣18 ؊/؊ ) were more resistant to lethal infection than were wild-type animals, and the phe Dengue virus (DENV), a flavivirus of the Flaviviridae family, is a serious public health problem in tropical and subtropical areas. In the last 60 years, the incidence, distribution, and clinical severity of dengue-related diseases have increased dramatically. 1,2 There are an estimated 50 million to 100 million DENV infections each year, of which approximately 500,000 are severe dengue hemorrhagic fever, and 24,000 result in death. 2,3 DENV is a single-stranded RNA virus that is transmitted to humans by Aedes mosquitoes, primarily Aedes aegypti. Infection with any of the four serotypes of DENV results in clinical symptoms that range from classic dengue fever to severe dengue hemorrhagic fever and shock syndrome, as defined by the World Health Organization. 4 Severe forms are life-threatening and are characterized by hemorrhagic manifestations, hemoconcentration, thrombocytopenia, and increased vascular permeability. 1,5-10 Despite growing public health concerns, currently there is no vaccine and no specific theraSupported in part by the

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Viral danger signals control CD1d de novo synthesis and NKT cell activation

et al. 2008

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The nonpolymorphic CD1 molecules present lipid antigens to T cells. In myeloid DC humans express five different CD1 proteins (CD1a-e; the corresponding CD1 genes are designated CD1A-E). A role for CD1d-restricted NKT cells in the control of virus infections has been delineated from clinical observations, mouse models and viral evasion mechanisms targeting CD1d. How NKT cells are activated by virus infections is unclear. We found that human myeloid DC differentially regulate CD1 antigen presentation in response to viral danger signals. Stimulation with type I IFN, viral TLR ligands or viruses strongly enhanced the number of CD1D transcripts in human myeloid DC but diminished the abundance of CD1A, CD1B and CD1E mRNA. These changes on the transcriptional level were mirrored by altered cellular distribution and increased surface expression of CD1d. As a consequence NKT cells were activated and showed a Th1-like response. Moreover, NKT cell activation in PBMC exposed to viral danger signals was dependent on human plasmacytoid DC which produce large amounts of IFN-a. In conclusion, our data indicate that viral danger signals trigger NKT cell activation by enhancing CD1d de novo synthesis through increasing the abundance of CD1D mRNA in human myeloid DC. IntroductionThe immune system detects viruses by recognizing antigens loaded on specialized surface molecules. The highly polymorphic MHC molecules bind to diverse peptides, traffic to the cell surface, and display this information to T cells [1]. Although distantly related to MHC proteins, the nonpolymorphic CD1 proteins constitute an evolutionarily distinct family of antigenpresenting molecules [2]. Humans express five different CD1 proteins (CD1a-e; the corresponding CD1 genes are designated CD1A-E). They are further divided into group 1 (CD1a-c) and group 2, which contains CD1d as the sole member. In contrast, CD1e is not expressed on the cell surface and is an intermediate form in terms of its homology to the other CD1 molecules. Accordingly, it is regarded as a group 3 CD1 molecule [3].By trafficking through endosomal compartments, CD1 proteins pick up antigens in a similar fashion to MHC class II molecules [4]. However, instead of peptides, CD1 molecules present lipids, glycolipids or lipopeptides of either foreign or self origin [2,5]. The CD1d-restricted NKT cells can also recognize a-galactosylceramide (aGalCer), a well-studied and highly potent CD1d ligand derived from a marine sponge [6,7]. These [18,25] or improves disease outcome [12,26]. Moreover, viruses subvert antigen presentation through CD1d [27][28][29][30][31][32][33], indicating its importance in antiviral immune defense.The mechanisms leading to activation of CD1d-restricted NKT cells in humans infected with viral pathogens are unknown. However, DC will play an important role as they link the innate and adaptive antiviral immunity [34]. DC sense invading viruses by detecting conserved pathogen-associated molecular patterns through a variety of different pattern recognition receptors, e.g. TLR...

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Innate immune response to encephalomyocarditis virus infection mediated by CD1d

Cited by 73 publications

References 67 publications

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

Selective activation, expansion, and monitoring of human iNKT cells with a monoclonal antibody specific for the TCR α‐chain CDR3 loop

A Detrimental Role for Invariant Natural Killer T Cells in the Pathogenesis of Experimental Dengue Virus Infection

Viral danger signals control CD1d de novo synthesis and NKT cell activation

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