NKT cells prevent chronic joint inflammation after infection with<i>Borrelia burgdorferi</i>

Tupin, Emmanuel; Benhnia, Mohammed Rafii‐El‐Idrissi; Kinjo, Yuki; Patsey, Rebeca L.; Lena, Christopher J.; Haller, Matthew C.; Caimano, Melissa J.; Imamura, Masakazu; Wong, Chi‐Huey; Crotty, Shane; Radolf, Justin D.; Sellati, Timothy J.; Kronenberg, Mitchell

doi:10.1073/pnas.0810519105

Cited by 88 publications

(87 citation statements)

References 42 publications

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“…Finally, the low prevalence of ABL prevents the analysis of susceptibility to pathogens dependent upon CD1-mediated immune responses but that infrequently lead to infections in humans (e.g., Borrelia burgdorferi or Leishmania spp.) (52)(53)(54). Notably, however, increased susceptibility to herpes viruses, a group of common pathogens, has not been reported in ABL.…”

Section: Discussionmentioning

confidence: 99%

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Zeißig¹,

Dougan²,

Barral³

et al. 2010

J. Clin. Invest.

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Abetalipoproteinemia (ABL) is a rare Mendelian disorder of lipid metabolism due to genetic deficiency in microsomal triglyceride transfer protein (MTP). It is associated with defects in MTP-mediated lipid transfer onto apolipoprotein B (APOB) and impaired secretion of APOB-containing lipoproteins. Recently, MTP was shown to regulate the CD1 family of lipid antigen-presenting molecules, but little is known about immune function in ABL patients. Here, we have shown that ABL is characterized by immune defects affecting presentation of self and microbial lipid antigens by group 1 (CD1a, CD1b, CD1c) and group 2 (CD1d) CD1 molecules. In dendritic cells isolated from ABL patients, MTP deficiency was associated with increased proteasomal degradation of group 1 CD1 molecules. Although CD1d escaped degradation, it was unable to load antigens and exhibited functional defects similar to those affecting the group 1 CD1 molecules. The reduction in CD1 function resulted in impaired activation of CD1-restricted T and invariant natural killer T (iNKT) cells and reduced numbers and phenotypic alterations of iNKT cells consistent with central and peripheral CD1 defects in vivo. These data highlight MTP as a unique regulator of human metabolic and immune pathways and reveal that ABL is not only a disorder of lipid metabolism but also an immune disease involving CD1.

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Section: Discussionmentioning

confidence: 99%

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Zeißig¹,

Dougan²,

Barral³

et al. 2010

J. Clin. Invest.

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“…Nonetheless, both ␥␦ and iNKT cell subsets rapidly produce various cytokines in response to infection (18,42), both manifest a previously activated phenotype in vivo as reflected in CD44 expression and a high turnover rate (16,35), and there is evidence in both for their indirect activation via TLR signaling on DC, which may enable the ␥␦ and iNKT cells to better activate both innate and adaptive immune responses (8,21,22). Like ␥␦ T-cell-deficient mice, iNKT-deficient mice have a reduced ability to clear Borrelia upon infection (37). Thus, both ␥␦ T cells and iNKT cells may function as transitional T cells that link the innate and adaptive immune responses.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, we measured the Borrelia burden from ear DNA using qPCR of the recA gene, which is chromosomal, whereas the previous study measured ospA, which is episomal. ␥␦ T cells share several parallels with invariant NKT (iNKT) cells, which also respond to B. burgdorferi, although the response by iNKT cells is via direct recognition of borrelial diacylglycerol antigens in a CD1d-restricted manner (17,37,40). Nonetheless, both ␥␦ and iNKT cell subsets rapidly produce various cytokines in response to infection (18,42), both manifest a previously activated phenotype in vivo as reflected in CD44 expression and a high turnover rate (16,35), and there is evidence in both for their indirect activation via TLR signaling on DC, which may enable the ␥␦ and iNKT cells to better activate both innate and adaptive immune responses (8,21,22).…”

Section: Discussionmentioning

confidence: 99%

Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

et al. 2011

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Little is known regarding the function of ␥␦ T cells, although they accumulate at sites of inflammation in infections and autoimmune disorders. We previously observed that ␥␦ T cells in vitro are activated by Borrelia burgdorferi in a TLR2-dependent manner. We now observe that the activated ␥␦ T cells can in turn stimulate dendritic cells in vitro to produce cytokines and chemokines that are important for the adaptive immune response. This suggested that in vivo ␥␦ T cells may assist in activating the adaptive immune response. We examined this possibility in vivo and observed that ␥␦ T cells are activated and expand in number during Borrelia infection, and this was reduced in the absence of TLR2. Furthermore, in the absence of ␥␦ T cells, there was a significantly blunted response of adaptive immunity, as reflected in reduced expansion of T and B cells and reduced serum levels of anti-Borrelia antibodies, cytokines, and chemokines. This paralleled a greater Borrelia burden in ␥␦-deficient mice as well as more cardiac inflammation. These findings are consistent with a model of ␥␦ T cells functioning to promote the adaptive immune response during infection.Infection with Borrelia burgdorferi, the causative agent of Lyme disease, can manifest in myriad ways in humans, among them a flulike illness, skin rash, cardiac inflammation with heart block, arthritis, and central nervous system involvement (29-34). Both innate and adaptive immunities are involved in the host defense against Borrelia infection, as witnessed by the involvement of Toll-like receptor 2 (TLR2) in response to Borrelia lipoproteins, such as the outer surface proteins (11), as well as the protective effect of antibodies (10). It is less clear how these two arms of the immune system are sequentially engaged during Borrelia infection and what cellular components might link them. In human Lyme arthritis, a clue to this may come from the appearance of a significant proportion of ␥␦ T cells in the inflamed synovium (38,39).The function of ␥␦ T cells in the immune system remains something of an enigma. Although their potential for generating a large array of T-cell receptor (TCR) rearrangements is as great as that of ␣␤ T cells, their actual selected repertoire is more limited, suggesting that their ligand(s) may be more limited (2, 6). ␥␦ T cells turn over in vivo at a high rate and can rapidly produce high levels of certain cytokines, such as gamma interferon (IFN-␥) or interleukin 17 (IL-17) (24, 35). They also express high levels of the death receptor ligand, Fas ligand (26). Collectively, these properties suggest that ␥␦ T cells might function to either initiate and/or downregulate the adaptive immune response.We have previously observed a strong proliferative response in vitro of ␥␦ T cells to B. burgdorferi, both from the human V␦1 subset that accumulates in inflamed synovium and from murine splenic ␥␦ T cells (7, 38). In both cases, the evidence suggested that the ␥␦ response to Borrelia was not direct but rather indirect via Borrelia stimulation o...

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“…Since that time, several microbial and even self-lipid iNKT Ags have been identified, although these are not as potent as a-GalCer. For example, diacylglycerols (DAGs) derived from the spirochete Borrelia burgdorferi [responsible for Lyme's disease (4)] and Streptococcus pneumoniae [causative agent of pneumonia (5,6)] were shown to activate iNKT cells directly. In addition, innate-like activation of iNKT cells upon bacterial and even viral infections were also reported, predominantly driven by IL-12 production from APCs (potentially in combination with IL-18 and dependent on TLR signaling) (7)(8)(9).…”

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confidence: 99%

Bacterial CD1d–Restricted Glycolipids Induce IL-10 Production by Human Regulatory T Cells upon Cross-Talk with Invariant NKT Cells

Venken

Decruy

Aspeslagh

et al. 2013

The Journal of Immunology

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Invariant NKT (iNKT) cells and CD4+CD25+FOXP3+ regulatory T cells (Tregs) are important immune regulatory T cells with Ag reactivity to glycolipids and peptides, respectively. However, the functional interplay between these cells in humans is poorly understood. We show that Tregs suppress iNKT cell proliferation induced by CD1d-restricted glycolipids, including bacterial-derived diacylglycerols, as well as by innate-like activation. Inhibition was related to the potency of iNKT agonists, making diacylglycerol iNKT responses very prone to suppression. Cytokine production by iNKT cells was differentially modulated by Tregs because IL-4 production was reduced more profoundly compared with IFN-γ. A compelling observation was the significant production of IL-10 by Tregs after cell contact with iNKT cells, in particular in the presence of bacterial diacylglycerols. These iNKT-primed Tregs showed increased FOXP3 expression and superior suppressive function. Suppression of iNKT cell responses, but not conventional T cell responses, was IL-10 dependent, suggesting that there is a clear difference in mechanism between the Treg-mediated inhibition of these cell types. Our data highlight a physiologically relevant interaction between human iNKT and Tregs upon pathogen-derived glycolipid recognition that has a significant impact on the design of iNKT cell–based therapeutics.

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NKT cells prevent chronic joint inflammation after infection withBorrelia burgdorferi

Cited by 88 publications

References 42 publications

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Primary deficiency of microsomal triglyceride transfer protein in human abetalipoproteinemia is associated with loss of CD1 function

Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

Bacterial CD1d–Restricted Glycolipids Induce IL-10 Production by Human Regulatory T Cells upon Cross-Talk with Invariant NKT Cells

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