scholarly journals Graft invariant natural killer T-cell dose predicts risk of acute graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Blood ◽  
2012 ◽  
Vol 119 (21) ◽  
pp. 5030-5036 ◽  
Author(s):  
Aristeidis Chaidos ◽  
Scott Patterson ◽  
Richard Szydlo ◽  
Mohammed Suhail Chaudhry ◽  
Francesco Dazzi ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Natural Killer ◽  
Inkt Cell ◽  
Inkt Cells ◽  
Cell Dose ◽  
Grade Ii ◽  
Clinically Significant ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4− iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4− iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4− iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4− iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4− iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.

scholarly journals Combination of NKT14m and Low Dose IL-12 Promotes Invariant Natural Killer T Cell IFN-γ Production and Tumor Control

2020 ◽  
Vol 21 (14) ◽  
pp. 5085
Author(s):  
Peng Guan ◽  
Robert Schaub ◽  
Kim E. Nichols ◽  
Rupali Das
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Low Dose ◽  
Inkt Cell ◽  
Tumor Control ◽  
Inkt Cells ◽  
Ifn Γ ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T (iNKT) cells are innate-like T lymphocytes characterized by the expression of an invariant T cell receptor (iTCR) that recognizes glycolipid antigens presented by the MHC I-like CD1d molecule. Following antigenic stimulation, iNKT cells rapidly produce large amounts of cytokines that can trans-activate dendritic cells (DC) and promote the anti-tumor functions of cytotoxic lymphocytes, such as natural killer (NK) and CD8 T cells. Additionally, iNKT cells can mediate robust and direct cytotoxicity against CD1d+ tumor targets. However, many tumors down-regulate CD1d and evade iNKT cell attack. To circumvent this critical barrier to iNKT cell anti-tumor activity, a novel monoclonal antibody (mAb), NKT14 has been recently developed. This agonistic antibody binds directly and specifically to the iTCR of murine iNKT cells. In the current study, we demonstrate that NKT14m mediates robust activation, cytokine production and degranulation of murine iNKT cells, in vitro. Consistently, NKT14m also promoted iNKT cell activation and immunomodulatory functions, in vivo. Finally, administration of NKT14m with low dose interleukin (IL)-12 further augmented iNKT cell IFN-γ production in vivo, and this combination conferred superior suppression of tumor cell growth compared to NKT14m or IL-12 alone. Together, these data demonstrate that a combination treatment consisting of low dose IL-12 and iTCR-specific mAb may be an attractive alternative to activate iNKT cell anti-tumor functions.

scholarly journals Cancer Immunotherapeutic Potential of NKTT320, a Novel, Invariant, Natural Killer T Cell-Activating, Humanized Monoclonal Antibody

2020 ◽  
Vol 21 (12) ◽  
pp. 4317 ◽  
Author(s):  
Nishant P. Patel ◽  
Peng Guan ◽  
Devika Bahal ◽  
Tanwir Hashem ◽  
Felix Scheuplein ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell ◽  
Natural Killer ◽  
Cell Activation ◽  
Cell Receptor ◽  
Inkt Cell ◽  
Humanized Monoclonal Antibody ◽  
Cancer Immunotherapeutic ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant natural killer T cells (iNKTs) directly kill tumor cells and trans-activate the anti-tumor functions of dendritic cells (DC), natural killer (NK) cells, and T and B cells. As such, iNKTs serve as a powerful tool for use in cell-based cancer immunotherapy. iNKT cell activation commonly requires engagement of the invariant T cell receptor (iTCR) by CD1d presenting glycolipid antigens. However, transformed cells often down-regulate CD1d expression, which results in a reduction of iNKT cell anti-tumor functions. One approach to circumvent this critical barrier to iNKT cell activation is to develop an agonistic antibody that binds directly to the iTCR without the requirement for CD1d-mediated antigen presentation. To this end, we have characterized the iNKT cell stimulatory properties of NKTT320, a novel, recombinant, humanized, monoclonal antibody that binds selectively and with high affinity to human iTCRs. Strikingly, immobilized NKTT320 mediated robust iNKT cell activation (upregulation of CD25 and CD69) and proliferation (carboxyfluorescein succinimidyl ester (CFSE) dilution), as well as Th1 and Th2 cytokine production. Additionally, iNKTs stimulated by plate-bound NKTT320 exhibited increased intracellular levels of granzyme B and degranulation (exposure of CD107 on the cell surface). Furthermore, both soluble and immobilized NKTT320 induced iNKT cell-mediated activation of bystander immune cells, suggesting that this novel anti-iTCR antibody facilitates both direct and indirect iNKT cell cytotoxicity. These studies are significant, as they provide a framework by which iNKT cell anti-cancer functions could be enhanced for therapeutic purposes.

scholarly journals Distinct bioenergetic features of human invariant natural killer T (iNKT) cells enable retained functions in nutrient-deprived states

2021 ◽  
Author(s):  
Priya Khurana ◽  
Chakkapong Burudpakdee ◽  
Stephan A. Grupp ◽  
Ulf H. Beier ◽  
David M. Barrett ◽  
...  
Keyword(s):  
Natural Killer ◽  
Metabolic Flux ◽  
Cytokine Production ◽  
Inkt Cell ◽  
Flux Analysis ◽  
Inkt Cells ◽  
Effector Functions ◽  
Functional Features ◽  
Invariant Natural Killer ◽  
Natural Killer T

ABSTRACTInvariant natural killer T (iNKT) cells comprise a unique subset of lymphocytes that are primed for activation and possess innate NK-like functional features. Currently, iNKT cell-based immunotherapies remain in early clinical stages, and little is known about the ability of these cells to survive and retain effector functions within the solid tumor microenvironment (TME) long-term. In conventional T cells (TCONV), cellular metabolism is linked to effector functions and their ability to adapt to the nutrient-poor TME. In contrast, the bioenergetic requirements of iNKT cells – particularly those of human iNKT cells – at baseline and upon stimulation are not well understood; neither is how these requirements affect cytokine production or anti-tumor effector functions. We find that unlike TCONV, human iNKT cells are not dependent upon glucose or glutamine for cytokine production and cytotoxicity upon stimulation with anti-CD3 and anti-CD28. Additionally, transcriptional profiling revealed that stimulated human iNKT cells are less glycolytic than TCONV and display higher expression of fatty acid oxidation (FAO) and adenosine monophosphate-activated protein kinase (AMPK) pathway genes. Furthermore, stimulated iNKT cells displayed higher mitochondrial mass and membrane potential relative to TCONV. Real-time Seahorse metabolic flux analysis revealed that stimulated human iNKT cells utilize fatty acids as substrates for oxidation more than stimulated TCONV. Together, our data suggest that human iNKT cells possess different bioenergetic requirements from TCONV and display a more memory-like metabolic program relative to effector TCONV. Importantly, iNKT cell-based immunotherapeutic strategies could co-opt such unique features of iNKT cells to improve their efficacy and longevity of anti-tumor responses.

Abstract 541: Specific Deletion of LDL Receptor--Related Protein on Macrophages Skews Cytokine Production by Invariant Natural Killer T Cells

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Roman Covarrubias ◽  
Amy S Major
Keyword(s):  
Natural Killer ◽  
Cell Activation ◽  
Ldl Receptor ◽  
Inkt Cell ◽  
Related Protein ◽  
Inkt Cells ◽  
Glycolipid Antigen ◽  
Invariant Natural Killer ◽  
Natural Killer T

Invariant Natural Killer T (iNKT) cells are specialized lymphocytes that when activated can regulate chronic inflammatory conditions and atherosclerotic processes. The activation of iNKT cells occurs when glycolipid antigens bind the MHC class-I like molecule CD1d present on antigen presenting cells (APCs). The pathways by which glycolipid antigens target CD1d for presentation and activation of iNKT cells remain unclear, yet the expression of surface receptors associated with lipid homeostasis, such as the LDL receptor (LDLr), have been implicated in the modulation of iNKT cell activation. The LDLr has been shown to modulate this process by binding apoE-containing lipoproteins, which can carry antigenic glycolipids for iNKT cell activation. The LDL receptor-related protein (LRP), a transmembrane receptor from the LDL receptor family of proteins, shares structural homology with LDLr and can bind a number of ligands including apoE-containing lipoproteins. We hypothesized that LRP can play an active role in glycolipid antigen presentation and subsequent activation of iNKT cells. Here, we demonstrate that LRP is preferentially expressed at high levels on F4/80 + macrophages, when compared to other APCs. We also show that a specialized subset of macrophages expressing CD169, known for their ability to present glycolipid antigen to iNKT cells, have increased levels of LRP when compared to CD169 - macrophages. Using mice with a targeted deletion of LRP in macrophages, we observed decreased activation of iNKT cells in vitro (24, 48 hours) and normal IFN-gamma but blunted IL-4 response in vivo. Further flow cytometric analysis showed normal surface expression of CD1d in LRP-cKO macrophages as well as normal uptake of fluorescently labeled glycolipid in vitro . Additionally, analysis of the iNKT cell compartment in LRP-cKO mice revealed intact numbers and percentages of iNKT cells and no homeostatic disruption as evidenced by absence of programmed death-1 and LY-49. Collectively, these data suggest that macrophage LRP contributes to early iNKT cell activation by enhancing early IL-4 responses.

scholarly journals TNF receptor associated factor 3 plays a key role in development and function of invariant natural killer T cells

2013 ◽  
Vol 210 (6) ◽  
pp. 1079-1086 ◽  
Author(s):  
Zuoan Yi ◽  
Laura L. Stunz ◽  
Gail A. Bishop
Keyword(s):  
Natural Killer ◽  
Developmental Stages ◽  
Critical Role ◽  
Inkt Cell ◽  
Tnf Receptor ◽  
Inkt Cells ◽  
Tcr Signaling ◽  
Associated Factor ◽  
Invariant Natural Killer ◽  
Natural Killer T

TCR signaling is a prerequisite for early stage development of invariant natural killer T (iNKT) cells, whereas IL-15 signaling is required for expansion and maturation at later stages. In this study, we show that TNF receptor associated factor 3 (TRAF3) plays a critical role in the transition between these two distinct signaling pathways and developmental stages. TRAF3-deficient iNKT cells in CD4CreTRAF3flox/flox (T-TRAF3−/−) mice exhibit defective up-regulation of T-bet and CD122, two critical molecules for IL-15 signaling, and as a consequence, IL-15–mediated iNKT cell proliferation and survival are impaired. Consistently, development of iNKT cells in T-TRAF3−/− mice shows a major defect at developmental stages 2 and 3, but not stages 0 and 1. We further demonstrated that defective T-bet up-regulation occurring during the stage 1 to stage 2 transition results from reduced TCR signaling in TRAF3−/− iNKT cells. In addition, mature TRAF3−/− iNKT cells displayed defective cytokine responses upon TCR stimulation. Collectively, our results reveal that by modulating the relative strength of TCR signaling, TRAF3 is an important regulator of iNKT cell development and functions.

scholarly journals Invariant Natural Killer T-cell Dynamics in Human Immunodeficiency Virus–associated Tuberculosis

2019 ◽  
Vol 70 (9) ◽  
pp. 1865-1874 ◽  
Author(s):  
Naomi F Walker ◽  
Charles Opondo ◽  
Graeme Meintjes ◽  
Nishtha Jhilmeet ◽  
Jon S Friedland ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiretroviral Therapy ◽  
Natural Killer ◽  
Inkt Cell ◽  
Inkt Cells ◽  
Cross Sectional ◽  
Immunodeficiency Virus ◽  
Invariant Natural Killer ◽  
Hiv 1 ◽  
Natural Killer T

Abstract Background Tuberculosis (TB) is the leading cause of mortality and morbidity in people living with human immunodeficiency virus (HIV) infection (PLWH). PLWH with TB disease are at risk of the paradoxical TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) when they commence antiretroviral therapy. However, the pathophysiology is incompletely understood and specific therapy is lacking. We investigated the hypothesis that invariant natural killer T (iNKT) cells contribute to innate immune dysfunction associated with TB-IRIS. Methods In a cross-sectional study of 101 PLWH and HIV-uninfected South African patients with active TB and controls, iNKT cells were enumerated using α-galactosylceramide-loaded CD1d tetramers and subsequently functionally characterized by flow cytometry. In a second study of 49 people with HIV type 1 (HIV-1) and active TB commencing antiretroviral therapy, iNKT cells in TB-IRIS patients and non-IRIS controls were compared longitudinally. Results Circulating iNKT cells were reduced in HIV-1 infection, most significantly the CD4+ subset, which was inversely associated with HIV-1 viral load. iNKT cells in HIV-associated TB had increased surface CD107a expression, indicating cytotoxic degranulation. Relatively increased iNKT cell frequency in patients with HIV-1 infection and active TB was associated with development of TB-IRIS following antiretroviral therapy initiation. iNKT cells in TB-IRIS were CD4+CD8– subset depleted and degranulated around the time of TB-IRIS onset. Conclusions Reduced iNKT cell CD4+ subsets as a result of HIV-1 infection may skew iNKT cell functionality toward cytotoxicity. Increased CD4– cytotoxic iNKT cells may contribute to immunopathology in TB-IRIS.

scholarly journals Liver X receptors regulate natural killer T cell population and antitumor activity in the liver of mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaori Endo-Umeda ◽  
Hiroyuki Nakashima ◽  
Shigeyuki Uno ◽  
Shota Toyoshima ◽  
Naoki Umeda ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Natural Killer ◽  
Cytokine Production ◽  
Nkt Cells ◽  
Inkt Cell ◽  
Cell Mediated Immunity ◽  
Inkt Cells ◽  
Nkt Cell ◽  
Natural Killer T

AbstractThe nuclear receptors liver X receptor α (LXRα) and LXRβ are lipid sensors that regulate lipid metabolism and immunity. Natural killer T (NKT) cells, a T cell subset expressing surface markers of both natural killer cells and T lymphocytes and involved in antitumor immunity, are another abundant immune cell type in the liver. The potential function of the metabolic regulators LXRα/β in hepatic NKT cells remains unknown. In this study, we examined the role of LXRα and LXRβ in NKT cells using mice deficient for LXRα and/or LXRβ, and found that hepatic invariant NKT (iNKT) cells are drastically decreased in LXRα/β-KO mice. Cytokine production stimulated by the iNKT cell activator α-galactosylceramide was impaired in LXRα/β-KO hepatic mononuclear cells and in LXRα/β-KO mice. iNKT cell-mediated antitumor effect was also disturbed in LXRα/β-KO mice. LXRα/β-KO mice transplanted with wild-type bone marrow showed decreased iNKT cells in the liver and spleen. The thymus of LXRα/β-KO mice showed a decreased population of iNKT cells. In conclusion, LXRα and LXRβ are essential for NKT cell-mediated immunity, such as cytokine production and hepatic antitumor activity, and are involved in NKT cell development in immune tissues, such as the thymus.

scholarly journals Human invariant natural killer T cells promote tolerance by preferential apoptosis induction of conventional dendritic cells

Haematologica ◽  
2021 ◽  
Author(s):  
Hannes Schmid ◽  
Emmanuelle M. Ribeiro ◽  
Kathy-Ann Secker ◽  
Silke Duerr-Stoerzer ◽  
Hildegard Keppeler ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Inkt Cells ◽  
Healthy Donors ◽  
Invariant Natural Killer ◽  
Natural Killer T

Graft-versus-host disease (GvHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. We recently showed in murine studies and in vitro human models that adoptively transferred invariant natural killer T (iNKT) cells protect from GvHD and promote graft-versus-leukemia effects. The cellular mechanisms underlying GvHD prevention by iNKT cells in humans, however, remain unknown. To study relevant cellular interactions, dendritic cells (DCs) were either generated from monocytes or isolated directly from blood of healthy donors or GvHD patients and co-cultured in a mixed lymphocyte reaction (MLR) with T cells obtained from healthy donors or transplantation bags. Addition of culture-expanded iNKT cells to the MLR induced DC apoptosis in a cell contact-dependent manner, thereby preventing T-cell activation and proliferation. Annexin V/PI staining and image stream assays showed that CD4+CD8-, CD4-CD8+ and double negative iNKT cells are similarly able to induce DC apoptosis. Further MLR assays revealed that conventional DCs (cDCs) but not plasmacytoid DCs (pDCs) could induce alloreactive T-cell activation and proliferation. Interestingly, cDCs were also more susceptible to apoptosis induced by iNKT cells, which correlates with their higher CD1d expression, leading to a bias in favor of pDCs. Remarkably, these results could also be observed in GvHD patients. We propose a new mechanism how ex vivo expanded human iNKT cells prevent alloreactivity of T cells. iNKT cells modulate T-cell responses by selective apoptosis of DC subsets, resulting in suppression of T-cell activation and proliferation while enabling beneficial immune responses through pDCs.

Effect of Graft and Early Posttransplantation Invariant Natural Killer T Cells on Disease Relapse Post Allogeneic Hematopoeitic Cell Transplantation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3823-3823
Author(s):  
Sauvi chang-Fong ◽  
Kristin Rathmann ◽  
Julie Pepe ◽  
Yasser Khaled ◽  
Alicja J Copik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Inkt Cell ◽  
Unrelated Donor ◽  
Inkt Cells ◽  
Cell Product ◽  
Cell Dose ◽  
Matched Sibling ◽  
Invariant Natural Killer ◽  
Donor Source

Abstract Invariant natural killer cells are immunomodulatory T cells with a proven effect in Graft versus Host disease. Recent data have shown that the infused iNKT cell dose is associated with decreased risk of aGVHD in matched sibling graft recipients. This study was conducted to assess the effect of the infused iNKT cell dose and early INKT recover at day 30 and 60 post HCT on relapse and GVHD. We also assessed the effect of INKT cells among patients receiving thymoglobulin as part of their HCT protocol. Methods: 48 adult allogeneic HCT recipients were enrolled on a single arm prospective trial between 2012 and 2014. All donors were mobilized with G-CSF per institutional and NMDP guidelines. Conditioning regimen consisted of Flu/Bu4 in the myeloablative setting and flu/Bu2 in RIC setting. Thymoglobulin at 1.5mg/kg/day x3 days was used for unrelated donor recipients. A small portion (2.5mL) of the donor peripheral blood stem cell product was collected prior to transplant and recipient peripheral blood (~10 mL) was collected on days +30, and +60 post HCT. Flow cytometric analysis was performed on the samples with an antibody cocktail that contained the following pre-conjugated monoclonal antibodies: CD56-PE (Miltenyi Biotech, Auburn, CA), CD3-APC, CD16-FITC, (Beckman Coulter, Brea, CA), CD19-PE-CY7 (BD Biosciences, San Jose, CA). For iNKT analysis and for CD4/CD8 analysis, 2 x 106 total cells were stained with CD3-APC, TCR Vα24-PE, TCR Vβ11-FITC (Beckman Coulter), CD4-APC-H7 and CD8-PE-CY7 (BD Biosciences). Data were acquired using BD FACSCanto II and analyzed with the FACSDiva software (BD Biosciences) to quantify CD3+ T cells, CD3+ CD56+ NK-like T cells, CD56+ CD16+ and CD56+ CD16- NK cells as well as CD19+ B cells. INKTs were quantified as CD3+, TCR Vα+, TCR Vβ+ lymphocytes. A total of 30,000 lymphocytes were collected for NK, T, and Bcell analysis. For iNKT, an end point of 200 iNKT or 500,000 total events was set. The graft and early cell subsets were assessed for their impact on acute GVHD and relapse. Results: 48 patients with a median age of 55 years received Flu/Bu4 (n= 29) and Flu/Bu2 (n=19). Donor source was a matched sibling (n=13, 27%) or a matched unrelated donor (n=35, 73%). The collected and infused graft cell doses are shown in table 1. Median time to Neutrophil and platelet engraftment was 11.5 and 18.8 days respectively. The propability of one year survival was 76% with a 1 year cumulative incidence of relapse of 34%. The pre-transplant parameters that predicted a more robust iNKT cell recovery by multivariate analysis were young recipient age, young donor age, dose of CD34 infused and RIC regimen (p<0.02 for all). A multivariate analysis to assess predictors of relapse showed that RIC (p=0.002), older donor age (p=0.03), and a smaller dose of infused INKT (p=0.012) were all significantly correlated with higher relapse rates. Day 30 and day 60 absolute iNKT and iNKT/T cell ratios were not predictors of relapse. None of the 22 patients with iNKT/T ratio of >10-3developed CMV reactivation. Conclusion: The infused iNKT cell dose in the peripheral graft inversely affects relapse rates post allogeneic HCT. This effect is independent of thymoglobulin use or donor source. Trials aiming at expanding the INT cell population in the infused grafts may help decrease risk of relapse post HCT. Table 1: Cellular Content of the Infused Graft Cell Subset Mean ± sd Median (min-max) CD3/kg infused 250 ± 111 251 (23-428) CD 34 infused 6.2 ± 2.1 6.0 (1.9-13.5) NK cell x106/kg infused 9.5 ± 11.0 6.6 (0-67) T cell x106/kg infused 192 ± 102 187 (0-516) B cell x106/kg infused 39.8 ± 33 35 (0-151) NKT x106/kg infused 9.5 ± 11.0 6.6 (0 -67) iNKT x106/kg infused 0.43 ± 0.7 0.23 (0-4.6) %CD34 product 0.99 ± 0.5 0.89 (0.15-2.7) %NK product 2.4 ± 1.5 1.9 (0.19-6.5) %T cell product 27.0 ± 11.0 27 (1.21-51.8) %NKT product 1.3 ± 1.2 1.0 (0.5- 5.9) %iNKT product 0.26 ± 0.7 0.12 (0 -4.5) %B cell product 5.4 ± 3.8 4.5 (0 -19.7) %WBC product 236 ± 100 209 (115-508) % Lymph product 32.4 ± 10.3 32 (13-51.8) NK cells, T cell, NKT and B cells are percentage of total nucleated cells iNKT cells are percentage of CD3+ cells Disclosures No relevant conflicts of interest to declare.

scholarly journals Invariant natural killer T cell–natural killer cell interactions dictate transplantation outcome after α-galactosylceramide administration

Blood ◽  
2009 ◽  
Vol 113 (23) ◽  
pp. 5999-6010 ◽  
Author(s):  
Rachel D. Kuns ◽  
Edward S. Morris ◽  
Kelli P. A. MacDonald ◽  
Kate A. Markey ◽  
Helen M. Morris ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
T Cell Activation ◽  
Cell Activation ◽  
Nk Cell ◽  
Killer Cell ◽  
Type I ◽  
Inkt Cells ◽  
Invariant Natural Killer ◽  
Natural Killer T

Abstract Invariant natural killer T cells (iNKT cells) have pivotal roles in graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL) effects. iNKT cells are activated through their T-cell receptors by glycolipid moieties (typically the α-galactosylceramide [α-GalCer] derivative KRN7000) presented within CD1d. We investigated the ability of modified α-GalCer molecules to differentially modulate alloreactivity and GVL. KRN7000 and the N-acyl variant, C20:2, were administered in multiple well-established murine models of allogeneic stem cell transplantation. The highly potent and specific activation of all type I NKT cells with C20:2 failed to exacerbate and in most settings inhibited GVHD late after transplantation, whereas effects on GVL were variable. In contrast, the administration of KRN7000 induced hyperacute GVHD and early mortality in all models tested. Administration of KRN7000, but not C20:2, was found to result in downstream interleukin (IL)-12 and dendritic cell (DC)–dependent natural killer (NK)– and conventional T-cell activation. Specific depletion of host DCs, IL-12, or donor NK cells prevented this pathogenic response and the induction of hyperacute GVHD. These data demonstrate the ability of profound iNKT activation to modulate both the innate and adaptive immune response via the DC–NK-cell interaction and raise concern for the use of α-GalCer therapeutically to modulate GVHD and GVL effects.

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