Role of CD1d in Coxsackievirus B3-Induced Myocarditis

Huber, Sally A.; Sartini, Danielle; Exley, Mark A.

doi:10.4049/jimmunol.170.6.3147

Cited by 83 publications

(96 citation statements)

References 42 publications

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“…However, T cells with more diverse TCRs also recognize CD1d; also, CD1d has been reported to have a signaling function that may be independent of T lymphocyte activity (33,34). In fact, in several experimental systems (35)(36)(37), analysis of Cd1d Ϫ/Ϫ and J␣18 Ϫ/Ϫ mice gave discordant results, suggesting either a role for CD1d-reactive T cells with more diverse TCRs or another function for CD1d besides antigen presentation. Consistent with this additional function for CD1d, MZ B cells from Cd1d Ϫ/Ϫ mice have reductions in Borrelia-specific IgM and IgG production in response to infection with the related spirochete, Borrelia hermsii (38).…”

Section: Discussionmentioning

confidence: 81%

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

Tupin

Benhnia

Kinjo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Borrelia burgdorferi is the etiologic agent of Lyme disease, a multisystem inflammatory disorder that principally targets the skin, joints, heart, and nervous system. The role of T lymphocytes in the development of chronic inflammation resulting from B. burgdorferi infection has been controversial. We previously showed that natural killer T (NKT) cells with an invariant (i) TCR ␣ chain (iNKT cells) recognize glycolipids from B. burgdorferi, but did not establish an in vivo role for iNKT cells in Lyme disease pathogenesis. Here, we evaluate the importance of iNKT cells for host defense against these pathogenic spirochetes by using V␣14i NKT cell-deficient (J␣18 ؊/؊ ) BALB/c mice. On tick inoculation with B. burgdorferi, J␣18 ؊/؊ mice exhibited more severe and prolonged arthritis as well as a reduced ability to clear spirochetes from infected tissues. V␣14i NKT cell deficiency also resulted in increased production of antibodies directed against both B. burgdorferi protein antigens and borrelial diacylglycerols; the latter finding demonstrates that anti-glycolipid antibody production does not require cognate help from V␣14i NKT cells. V␣14i NKT cells in infected wild-type mice expressed surface activation markers and produced IFN␥ in vivo after infection, suggesting a participatory role for this unique population in cellular immunity. Our data are consistent with the hypothesis that the antigen-specific activation of V␣14i NKT cells is important for the prevention of persistent joint inflammation and spirochete clearance, and they counter the long-standing notion that humoral rather than cellular immunity is sufficient to facilitate Lyme disease resolution.cytokines ͉ glycolipids ͉ Lyme disease ͉ spirochetes

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Section: Discussionmentioning

confidence: 81%

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

Tupin

Benhnia

Kinjo

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…Mice that lack CD1d or invariant NKT are more susceptible to specific infections, such as picornaviruses, 83 herpes simplex virus, 84 cerebral (though not systemic) malaria, 85 or Pseudomonas aeruginosa, 86 whereas in other circumstances a lack of NKT cells appears to ameliorate disease, such as viral myocarditis 87 or respiratory syncitia virus infection. 88 Of most interest to hepatologists is the role these cells might play in viral and other forms of hepatitis.…”

Section: Role In Infections Of the Livermentioning

confidence: 99%

To be or not to be NKT: Natural killer T cells in the liver

2004

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N KT cells are a diverse group of cells that share features of both classical T cells and natural killer (NK) cells, and have similarly diverse functions. One of the complexities in understanding NKT cells involves sorting through the various terminology that has been applied to them in the emerging literature. 1,2 Functionally, a major subset of these cells are defined by reactivity against CD1d, which is one of five known glycolipid-binding nonpolymorphic major histocompatibility complex class 1-like glycoproteins: CD1a through e. 3 These glycoproteins appear to have evolved to facilitate recognition of nonprotein antigens-specifically glycolipid antigens, including those present in the cell walls of mycobacterial species. CD1d is constitutively expressed on a number of hematopoietic-derived antigenpresenting cell (APC) types-including B cells and myeloid cells-and can be expressed by human T cells as well as healthy hepatocytes. Physiological ligands for CD1d remain poorly defined, although both glycolipids and hydrophobic peptides bind to CD1 family molecules. 4,5 Most antigen studies have used the synthetic glycolipid ␣-galactosylceramide (␣GalCer), which binds to CD1d and activates a specific subset of both murine and human NKT cells in vitro and in vivo. 5,6 CD1d is remarkably conserved across mammalian species, with mouse and human CD1d having greater than 90% sequence homology. 7 Consequently, murine CD1d-reactive T cells recognize human CD1d, and vice versa. 8 After activation, NKT cells are highly versatile and can produce large amounts of interferon gamma (IFN-␥) and interleukin (IL)-4 9,10 as prototypic type 1 and type 2 cytokines, respectively, as well as display NK/lymphokine-activated killing-like FasL-mediated or perforin-dependent CD1d-specific cytotoxicity 11-14 thus potentially contributing to protective and pathogenic responses against multiple infectious agents and tumors.CD1d is expressed by dendritic cells (DCs), and ␣Gal-Cer-loaded DCs mediate activation of invariant NKT cells. [15][16][17][18] Although peripheral NKT cells can recognize and respond to other CD1d ϩ cells, their in vivo activation may be initiated by interactions with DCs and possibly B cells. The interactions between invariant NKT cells and DCs share many features of interactions between conventional CD4 ϩ T cells and DCs. DCs pulsed with ␣GalCer stimulate NKT cells through T cell receptor (TCR) ligation. 2,19,20 NKT cell activation and IFN-␥ production are markedly enhanced by DC-produced IL-12, with an increase in the IL-12 receptor on activated NKT cells. 15,21,22 Conversely, invariant NKT cells also interact with ␣Gal-Cer-loaded DCs to enhance CD4 ϩ and CD8 ϩ T-cell responses 16,17,23,24 and with B cells to provide help for antibody production. 25 However, ␣Galcer is not a physiological antigen, and it is not yet clear whether physiological NKT-DC interactions are mediated by specific CD1d-presented antigens or are antigen independent.The classical CD1d-reactive NKT cell population expresses a highly restricted TCR r...

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“…Increasingly, in vivo studies show that V␣14 Ϫ CD1-restricted T cells have immunoregulatory functions that are distinct from V␣14 ϩ NK T cells. For example, in a murine model of myocarditis caused by Coxsackie virus, the inflammatory response depended on CD1d expression but was not affected by the deletion of T cells expressing the V␣14J␣18 gene (34). Likewise, hepatic inflammation in a mouse model of hepatitis B was shown to depend on CD1, but the effector T cells did not express V␣14 TCRs and did not stain with CD1d-␣GalCer tetramers (35).…”

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confidence: 98%

CD1d-restricted T cell activation by nonlipidic small molecules

Rhijn

Young

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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In addition to NK T cells expressing invariant V␣14 or V␣24 T cell receptors (TCRs), the CD1d-restricted T cell repertoire is comprised of T cells with diverse TCRs that mediate inflammation during autoimmune and infectious disease. Here we describe the isolation of human V␣24 ؊ T cells that are activated by antigen and CD1d. Mass spectrometric and NMR studies revealed that the stimulatory compounds were neither peptidic nor lipidic but instead were composed of sulfur and aromatic hydrocarbon rings, corresponding to the general structure of phenyl pentamethyldihydrobenzofuran sulfonates. Studies of the molecular mechanism of T cell activation showed that a clonotypic V␣2͞V␤21 TCR transmitted activating signals, which were highly specific for hydroxylation and methylation patterns at the terminal structures of stimulatory compounds. These studies provide evidence for noninvariant CD1d-restricted T cells in humans and identify the complete molecular structure of a nonlipidic small molecule that activates T cells through an ␣␤ TCR.

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Role of CD1d in Coxsackievirus B3-Induced Myocarditis

Cited by 83 publications

References 42 publications

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

To be or not to be NKT: Natural killer T cells in the liver

CD1d-restricted T cell activation by nonlipidic small molecules

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