A Single Subset of Dendritic Cells Controls the Cytokine Bias of Natural Killer T Cell Responses to Diverse Glycolipid Antigens

Arora, Pooja; Baena, Andrés; Yu, Karl O. A.; Saini, Neeraj Kumar; Kharkwal, Shalu Sharma; Goldberg, Michael F.; Kunnath-Velayudhan, Shajo; Carreño, Leandro J.; Venkataswamy, Manjunatha M.; Kim, John; Lázár‐Molnár, Eszter; Lauvau, Grégoire; Chang, Young Tae; Liu, Zheng; Bittman, Robert; Al‐Shamkhani, Aymen; Cox, Liam R.; Jervis, P. J.; Veerapen, Natacha; Besra, Gurdyal S.; Porcelli, Steven A.

doi:10.1016/j.immuni.2013.12.004

Cited by 92 publications

(137 citation statements)

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“…2B). Moreover, using labeled a-GalCer, we observed that compared with CD8a 2 DCs, CD8a + DCs more efficiently incorporate a-GalCer in vivo, a finding in line with Arora et al (25) (Supplemental Fig. 2C).…”

Section: Cd8asupporting

confidence: 91%

“…In the mouse system, DCs in the spleen, an important site of immune responses to blood-borne Ag, are mainly composed of CD8a + DCs, a subset specialized in Ag crosspresentation, and of CD8a 2 DCs, a subset more efficient at presenting Ag on MHC class II (24). Recent findings indicated that CD8a + DCs are particularly potent to activate iNKT cells (25) and to trigger iNKT cell-based innate immune responses (26,27). These data, and the fact that CD8a + DCs excel in Ag crosspresentation, prompted us to actively deliver a-GalCer and Ag to CD8a + DCs in vivo.…”

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confidence: 99%

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Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Macho-Fernandez

Cruz

Ghinnagow

et al. 2014

The Journal of Immunology

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Immunotherapy aiming at enhancing innate and acquired host immunity is a promising approach for cancer treatment. The invariant NKT (iNKT) cell ligand α-galactosylceramide (α-GalCer) holds great promise in cancer therapy, although several concerns limit its use in clinics, including the uncontrolled response it promotes when delivered in a nonvectorized form. Therefore, development of delivery systems to in vivo target immune cells might be a valuable option to optimize iNKT cell–based antitumor responses. Using dendritic cell (DC)–depleted mice, DC transfer experiments, and in vivo active cell targeting, we show that presentation of α-GalCer by DCs not only triggers optimal primary iNKT cell stimulation, but also maintains secondary iNKT cell activation after challenge. Furthermore, targeted delivery of α-GalCer to CD8α+ DCs, by means of anti-DEC205 decorated nanoparticles, enhances iNKT cell–based transactivation of NK cells, DCs, and γδ T cells. We report that codelivery of α-GalCer and protein Ag to CD8α+ DCs triggers optimal Ag-specific Ab and cytotoxic CD8+ T cell responses. Finally, we show that targeting nanoparticles containing α-GalCer and Ag to CD8α+ DCs promotes potent antitumor responses, both in prophylactic and in therapeutic settings. Our data may have important implications in tumor immunotherapy and vaccine development.

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Section: Cd8asupporting

confidence: 91%

mentioning

confidence: 99%

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Macho-Fernandez

Cruz

Ghinnagow

et al. 2014

The Journal of Immunology

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“…Administration of synthetic CD1d-restricted lipid agonists (typically αGalCer) in vivo has been shown to rapidly activate iNKT cells, as a result of lipid-CD1d complex presentation by CD8α + DCs [21,22]. Activated iNKT cells upregulate costimulatory molecules, including CD40L, and within a few hours release considerable quantities of different type 1 and type 2 cytokines that, in turn, activate NK cells and induce DC maturation [21,23,24].…”

Section: Introductionmentioning

confidence: 99%

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

2014

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T-cell help to B lymphocytes is one of the most important events in adaptive immune responses in health and disease. It is generally delivered by cognate CD4 + T follicular helper (T FH ) cells via both cell-to-cell contacts and soluble mediators, and it is essential for both the clonal expansion of antibody (Ab)-secreting B cells and memory B-cell formation. CD1d-restricted invariant natural killer T (iNKT) cells are a subset of innate-like T lymphocytes that rapidly respond to stimulation with specific lipid antigens (Ags) that are derived from infectious pathogens or stressed host cells. Activated iNKT cells produce a wide range of cytokines and upregulate costimulatory molecules that can promote activation of dendritic cells (DCs), natural killer (NK) cells, and T cells. A decade ago, we discovered that iNKT cells can help B cells to proliferate and to produce IgG Abs in vitro and in vivo. This adjuvant-like function of Ag-activated iNKT cells provides a flexible set of helper mechanisms that expand the current paradigm of T-cell-B-cell interaction and highlights the potential of iNKT-cell targeting vaccine formulations.Keywords: B-cell help r CD1d r T follicular helper cells r vaccines IntroductionThe production of neutralizing antibodies (Abs) by B cells represents a major parameter of host defense against infectious pathogens and is a key component of protective immune responses elicited by vaccines [1]. The innate and adaptive arms of the immune system are functionally separated, but seem to be highly coordinated to ensure an optimal outcome of immune responses. Although innate and adaptive immune cells are endowed with very distinct functions and timing of response, there are specialized lymphocyte subsets that straddle the two programs, and these cells have been defined as innate-like lymphocytes [2]. CD1d-rectricted invariant Vα14 natural killer T (iNKT) cells are one of the best characterized types of innate-like T lymphocytes, which display multiple effector functions upon activation [3]. Here, we review the mechanisms through which iNKT cells help B cells to promote Ab production and memory formation.Correspondence: Dr. Paolo Dellabona e-mail: dellabona.paolo@hsr.itThe TD and TI paradigm of the B-cell response B-cell responses are generally described as T-dependent (TD) or T-independent (TI), based on the requirement for T-cell help for Ab production. TD responses are induced by protein antigens (Ags) that are recognized by specific B cells in the presence of cognate T-cell help, which is provided by a specialized subset of CD4 + T helper (Th) cells called T follicular helper (T FH ) cells [4]. Ags reach the follicles, the B-cell zone of secondary lymphoid organs, and activate B cells upon binding to the specific B-cell receptors (BCRs [5]). This leads to Ag internalization, presentation of the processed Ag peptides into MHC class II (MHC II) molecules, and migration of the activated B cells to the border of the T-B-cell zone [4]. T FH cells are induced in the T-cell zone by dendritic cells (DCs) t...

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“…Some data suggest that Th1 responses depend on prolonged antigenic stimulation of iNKT cells, and this may be due to several factors, including enhanced GSL chemical stability in vivo, more stable binding of the GSL to CD1d, or increased TCR affinity for the GSL complex with CD1d (17). Alternatively, GSLs may have differential effects on antigen-presenting cells (APCs), for example, by trafficking to different components of the cell and inducing the expression of different cell surface molecules that influence immunity (27).…”

Section: Gsl Activation Of Inkt Cells Alters the Immune Responsementioning

confidence: 99%

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

Birkholz

Howell

Kronenberg

2015

Journal of Biological Chemistry

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Glycosphingolipids are a subgroup of glycolipids that contain an amino alcohol sphingoid base linked to sugars. They are found in the membranes of cells ranging from bacteria to vertebrates. This group of lipids is known to stimulate the immune system through activation of a type of white blood cell known as natural killer T cell (NKT cell). Here we summarize the extensive research that has been done to identify the structures of natural glycolipids that stimulate NKT cells and to determine how these antigens are recognized. We also review studies designed to understand how glycolipid variants, both natural and synthetic, can alter the responses of NKT cells, leading to dramatic changes in the global immune response.

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A Single Subset of Dendritic Cells Controls the Cytokine Bias of Natural Killer T Cell Responses to Diverse Glycolipid Antigens

Cited by 92 publications

References 38 publications

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

Targeted Delivery of α-Galactosylceramide to CD8α+ Dendritic Cells Optimizes Type I NKT Cell–Based Antitumor Responses

iNKT‐cell help to B cells: A cooperative job between innate and adaptive immune responses

The Alpha and Omega of Galactosylceramides in T Cell Immune Function

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