scholarly journals Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d

2021 ◽  
Vol 118 (34) ◽  
pp. e2104420118
Author(s):  
Catarina F. Almeida ◽  
Dylan G. M. Smith ◽  
Tan-Yun Cheng ◽  
Chris M. Harpur ◽  
Elena Batleska ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Nkt Cells ◽  
Short Chain ◽  
Spectrometric Analysis ◽  
Type I ◽  
Type Ii ◽  
Sulfa Drugs ◽  
Nkt Cell ◽  
Sulfa Drug

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αβ T cell receptors (TCR) and recognize α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells), but our knowledge of the antigens for type II NKT cells is limited. An early study identified a nonlipidic NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa drugs, but its mechanism of NKT cell activation remained unknown. Here, we demonstrate that a range of pentamethylbenzofuransulfonates (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug–like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d tetramers identified type II NKT cell populations expressing αβTCRs and γδTCRs, including those with variable and joining region gene usage (TRAV12-1–TRAJ6) that was conserved across donors. By trapping a CD1d–type II NKT TCR complex for direct mass-spectrometric analysis, we detected molecules that allow the binding of CD1d to TCRs, finding that both selected PBF family members and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that nonlipidic small molecules, which resemble sulfa drugs implicated in systemic hypersensitivity and drug allergy reactions, are targeted by a polyclonal population of type II NKT cells in a CD1d-restricted manner.

scholarly journals Benzofuran sulfonates and small self-lipid antigens activate type II NKT cells via CD1d

2021 ◽  
Author(s):  
CF Almeida ◽  
D Smith ◽  
T-Y Cheng ◽  
C Harpur ◽  
E Batleska ◽  
...  
Keyword(s):  
T Cell ◽  
Small Molecules ◽  
Nkt Cells ◽  
Short Chain ◽  
Type I ◽  
Type Ii ◽  
Sulfa Drugs ◽  
Nkt Cell ◽  
Sulfa Drug ◽  
Lipid Antigens

AbstractNatural Killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αβ T cell receptors (TCR) and recognise α-galactosylceramides. However, CD1d also presents structurally distinct lipids to NKT cells expressing diverse TCRs (type II NKT cells) but our knowledge of the antigens for type II NKT cells is limited. An early study identified an NKT cell agonist, phenyl pentamethyldihydrobenzofuransulfonate (PPBF), which is notable for its similarity to common sulfa-drugs, but its mechanism of NKT-cell activation remained unknown. Here we demonstrate that a range of pentamethylbenzofuransulfonate (PBFs), including PPBF, activate polyclonal type II NKT cells from human donors. Whereas these sulfa drug-like molecules might have acted pharmacologically on cells, here we demonstrate direct contact between TCRs and PBF-treated CD1d complexes. Further, PBF-treated CD1d-tetramers identified type II NKT cell populations cells expressing αβ and γδTCRs, including those with variable and joining region gene usage (TRAV12-1–TRAJ6) that was conserved across donors. By trapping a CD1d-type II NKT TCR complex for direct mass spectrometric analysis, we detected molecules that allow binding of CD1d to TCRs, finding that both PBF and short-chain sphingomyelin lipids are present in these complexes. Furthermore, the combination of PPBF and short-chain sphingomyelin enhances CD1d tetramer staining of PPBF-reactive T cell lines over either molecule alone. This study demonstrates that non-lipidic small molecules, that resemble sulfa-drugs implicated in systemic hypersensitivity and drug allergy reactions, activate a polyclonal population of type II NKT cells in a CD1d-restricted manner.Significance StatementWhereas T cells are known to recognize peptide, vitamin B metabolite or lipid antigens, we identify several non-lipidic small molecules, pentamethylbenzofuransulfonates (PBFs), that activate a population of CD1d-restricted NKT cells. This represents a breakthrough in the field of NKT cell biology. This study also reveals a previously unknown population of PBF-reactive NKT cells in healthy individuals with stereotyped receptors that paves the way for future studies of the role of these cells in immunity, including sulfa-drug hypersensitivity.

scholarly journals Type I NKT cells protect (and type II NKT cells suppress) the host's innate antitumor immune response to a B-cell lymphoma

Blood ◽  
2008 ◽  
Vol 111 (12) ◽  
pp. 5637-5645 ◽  
Author(s):  
Gourapura J. Renukaradhya ◽  
Masood A. Khan ◽  
Marcus Vieira ◽  
Wenjun Du ◽  
Jacquelyn Gervay-Hague ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Nkt Cell ◽  
Tumor Bearing

Abstract Natural killer T (NKT) cells are a T-cell subpopulation known to possess immunoregulatory functions and recognize CD1d molecules. The majority of NKT cells express an invariant T-cell receptor (TCR) α chain rearrangement (Vα14Jα18 in mice; Vα24Jα18 in humans) and are called type I NKT cells; all other NKT cells are type II. In the current study, we have analyzed the roles for these NKT-cell subsets in the host's innate antitumor response against a murine B-cell lymphoma model in vivo. In tumor-bearing mice, we found that type I NKT cells conferred protection in a CD1d-dependent manner, whereas type II NKT cells exhibited inhibitory activity. Pro- and anti-inflammatory cytokines secreted by splenocytes from tumor-bearing mice correlated with tumor progression. Myeloid cells (CD11b+Gr1+) were present in large numbers at the tumor site and in the spleen of tumor-bearing type I NKT–deficient mice, suggesting that antitumor immunosurveillance was inhibited by CD11b+Gr1+ cells. Overall, these data suggest that there are distinct roles for NKT-cell subsets in response to a B-cell lymphoma in vivo, pointing to potential novel targets to be exploited in immunotherapeutic approaches against blood cancers.

Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma

2011 ◽  
Vol 301 (6) ◽  
pp. L975-L984 ◽  
Author(s):  
Guqin Zhang ◽  
Hanxiang Nie ◽  
Jiong Yang ◽  
Xuhong Ding ◽  
Yi Huang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Airway Inflammation ◽  
Cell Activation ◽  
Cell Function ◽  
Allergic Airway Inflammation ◽  
Nkt Cells ◽  
Chronic Inflammatory Disease ◽  
Type I ◽  
Type Ii ◽  
Nkt Cell

Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

scholarly journals The Role of NKT Cells in Glioblastoma

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1641
Author(s):  
Emily E. S. Brettschneider ◽  
Masaki Terabe
Keyword(s):  
Immune Responses ◽  
Cell Activity ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Central Nervous System Diseases ◽  
Nkt Cell ◽  
Lipid Antigens ◽  
Immunoregulatory Mechanisms

Glioblastoma is an aggressive and deadly cancer, but to date, immunotherapies have failed to make significant strides in improving prognoses for glioblastoma patients. One of the current challenges to developing immunological interventions for glioblastoma is our incomplete understanding of the numerous immunoregulatory mechanisms at play in the glioblastoma tumor microenvironment. We propose that Natural Killer T (NKT) cells, which are unconventional T lymphocytes that recognize lipid antigens presented by CD1d molecules, may play a key immunoregulatory role in glioblastoma. For example, evidence suggests that the activation of type I NKT cells can facilitate anti-glioblastoma immune responses. On the other hand, type II NKT cells are known to play an immunosuppressive role in other cancers, as well as to cross-regulate type I NKT cell activity, although their specific role in glioblastoma remains largely unclear. This review provides a summary of our current understanding of NKT cells in the immunoregulation of glioblastoma as well as highlights the involvement of NKT cells in other cancers and central nervous system diseases.

scholarly journals Identification of Previously Unrecognized CD1d-Restricted Peripheral T Cell Lymphomas (PTCLs) in Mouse and Human Reveals Blocking Anti-CD1d Monoclonal Antibodies As a New Therapeutic Possibility in PTCLs

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4485-4485
Author(s):  
Emmanuel Bachy ◽  
Mirjam Urb ◽  
Gabriel Bricard ◽  
Shilpi Jayaswal ◽  
Remy Robinot ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Profile Analysis ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Cell Of Origin ◽  
Gamma Delta ◽  
Inkt Cells ◽  
T Cell Lymphomas

Abstract Background. Peripheral T-cell lymphomas (PTCLs) originate from post-thymic T cells but compared to B-cell lymphomas the exact cell of origin is usually unknown except for angioimmunoblastic T-cell lymphoma arising from a follicular helper T-cell. Furthermore, no recurrent cytogenetic or molecular abnormalities are identified in PTCLs. Recently, recurrent impairment of the p53 pathway has been pointed out in PTCLs. However, p53 knockout (KO) mice are known to develop immature thymic T-cell lymphomas and solid tumors but surprisingly PTCLs have not been reported for more than 20 years in those mice. NKT cells are a T-cell subset responsive to glycolipids presented by CD1d, a major histocompatibility complex (MHC) class I-like antigen-presenting molecule, in contrast to conventional T cells, which recognize peptide antigens. Two types of NKT cells have been described so far: type I or invariant NKT cells (iNKT) that express a Valpha14-Jalpha18 (in mice) or Valpha24-Jalpha18 (in humans) constant chain and type II NKT cells that express a variable TCR but are CD1d-dependent as well. Most type II NKT cells are of alpha/beta phenotype but CD1d-restricted gamma/delta T cells have also been described in mice and humans. Methods. The development of PTCLs in p53 KO mice (B6.129S2-Trp53tm1Tyj/J) was studied. Identification of PTCLs was made by immunohistochemistry and flow cytometry analysis. Gene expression profile analysis (GeneChip Mouse Genome 430 2.0 array, Affymetrix) was performed to characterize lymphomas developed in the mouse model. Transfer experiments were done by intravenously retro-orbital injection into syngeneic, immunocompetent C57Bl/6J WT animals or immunocompromised CD3ε-/- mice. Therapeutic trials in mice were performed with the use of blocking anti-CD1d monoclonal antibodies (mAb) (clone HB323; BioXcell). Results. We found that p53 KO mice developed well-known and characterized thymic T-cell lymphomas and solid tumors as previously described. However, about 20% of p53 KO mice spontaneously developed a previously unrecognized entity of PTCLs originating from CD1d-restricted iNKT cells (ie type I NKT cells) referred to as NKTLs for NKT lymphomas thereafter. Both alpha-galactosylceramide-CD1d tetramer staining and unique Valpha14-Jalpha18 TCR rearrangement confirmed the iNKT nature of these lymphomas. Chronic injection of Streptococcus pneumoniae (Spn), reported to express glycolipid antigens activating NKT cells, significantly increased the incidence of these NKTLs compared to a control group of p53 KO mice injected with PBS (P=0.03). Gene expression profile analysis indicated a significant down-regulation of genes in the TCR signaling pathway of NKTLs (false discovery rate q-value=0.01 by gene set enrichment analysis) suggesting an underlying antigenic chronic stimulation as previously reported in chronically activated T cells (Figure 1). Moreover, NKTLs were characterized by upregulation of PD-1 and loss of NK1.1 expression compared to resting NKT cells (P<0.01 for both), which are features of activated and anergic iNKT cells. Altogether, those data indicate that NKTLs in mice could arise from chronically activated iNKT cells by endogenous or exogenous glycolipids. Furthermore, in vivo TCR/CD1d interactions were required for NKTLs survival after transfer in recipient mice and the use of blocking anti-CD1d mAb significantly prolonged mice overall survival (logrank P<0.001, Figure 2). We did not identify human PTCLs arising from type I iNKT cells by using alphaGalCer-CD1d tetramer staining. However, using sulfatide-loaded CD1d tetramers (ie another type of glycolipid-CD1d tetramer identifying type II NKT cells), we identified CD1d-restricted human PTCLs among gamma/delta hepatosplenic T-cell lymphomas (HSTLs) and PTCL-not otherwise specified (PTCL-NOS) expressing the Vd1 TCR but not the Vd2 TCR (Figure 3). Conclusion. This demonstrates for the first time the existence of human PTCLs arising from gamma/delta CD1d-restricted type II NKT cells. These results refine the classification of PTCLs in humans by identifying a new cell of origin and pave the way for the development of blocking anti-CD1d antibodies for therapeutic purposes. Figure 1. Figure 1. Figure 2. Figure 2. Figure 3. Figure 3. Disclosures No relevant conflicts of interest to declare.

scholarly journals Distinct CD1d docking strategies exhibited by diverse Type II NKT cell receptors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Catarina F. Almeida ◽  
Srinivasan Sundararaj ◽  
Jérôme Le Nours ◽  
T. Praveena ◽  
Benjamin Cao ◽  
...  
Keyword(s):  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Nkt Cell ◽  
Lipid Antigens ◽  
Microbial Antigen ◽  
Health And Disease ◽  
Lipid Antigen ◽  
And Function ◽  
Antigen Presenting

AbstractType I and type II natural killer T (NKT) cells are restricted to the lipid antigen-presenting molecule CD1d. While we have an understanding of the antigen reactivity and function of type I NKT cells, our knowledge of type II NKT cells in health and disease remains unclear. Here we describe a population of type II NKT cells that recognise and respond to the microbial antigen, α-glucuronosyl-diacylglycerol (α-GlcADAG) presented by CD1d, but not the prototypical type I NKT cell agonist, α-galactosylceramide. Surprisingly, the crystal structure of a type II NKT TCR-CD1d-α-GlcADAG complex reveals a CD1d F’-pocket-docking mode that contrasts sharply with the previously determined A’-roof positioning of a sulfatide-reactive type II NKT TCR. Our data also suggest that diverse type II NKT TCRs directed against distinct microbial or mammalian lipid antigens adopt multiple recognition strategies on CD1d, thereby maximising the potential for type II NKT cells to detect different lipid antigens.

scholarly journals Cutaneous Immunization Rapidly Activates Liver Invariant Vα14 NKT Cells Stimulating B-1 B Cells to Initiate T Cell Recruitment for Elicitation of Contact Sensitivity

2003 ◽  
Vol 198 (12) ◽  
pp. 1785-1796 ◽  
Author(s):  
Regis A. Campos ◽  
Marian Szczepanik ◽  
Atsuko Itakura ◽  
Moe Akahira-Azuma ◽  
Stephane Sidobre ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Activation ◽  
Nkt Cells ◽  
Effector T Cells ◽  
Cell Passage ◽  
Contact Sensitivity ◽  
Nkt Cell ◽  
Cell Recruitment ◽  
Deficient Mice ◽  
Skin Immunization

T cell recruitment to elicit contact sensitivity (CS) requires a CS-initiating process mediated by B-1 cells that produce IgM, which activates complement to promote T cell passage into the tissues. We now show that Vα14i NKT cells induce B-1 cell activation likely by releasing IL-4 early postimmunization. The CS initiation process is absent in Jα18−/− and CD1d−/− NKT cell–deficient mice and is reconstituted by populations enriched for Vα14i NKT cells. Transfers are not effective if cells are derived from IL-4−/− mice. Staining with specific tetramers directly showed that hepatic Vα14i NKT cells increase by 30 min and nearly double by 2 h postimmunization. Transfer of immune B-1 cells also reconstitutes CS responses in NKT cell–deficient mice. The B-1 cells act downstream of the Vα14i NKT cells to restore CS initiation. In addition, IL-4 given systemically to Jα18−/− or CD1d−/− NKT cell–deficient mice reconstitutes elicitation of CS. Further, splenocytes from immune Jα18−/− mice produce less antigen (Ag)-specific IgM antibodies compared with sensitized WT mice. Together these findings indicate that very early after skin immunization Vα14i NKT cells are stimulated to produce IL-4, which activates B-1 cells to produce Ag-specific IgM, subsequently needed to recruit effector T cells for elicitation of CS responses.

scholarly journals Multi-omics approach identifies novel age-, time- and treatment-related immunopathological signatures in MIS-C and pediatric COVID-19

2021 ◽  
Author(s):  
Keith Sacco ◽  
Riccardo Castagnoli ◽  
Svetlana Vakkilainen ◽  
Can Liu ◽  
Ottavia M. Delmonte ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Confounding Factor ◽  
Type I ◽  
Type Ii ◽  
Significant Morbidity ◽  
Mutation Load ◽  
Th2 Responses ◽  
Inflammatory Syndrome

Pediatric COVID-19 (pCOVID-19) is rarely severe, however a minority of SARS-CoV-2-infected children may develop MIS-C, a multisystem inflammatory syndrome with significant morbidity. In this longitudinal multi-institutional study, we used multi-omics to identify novel time- and treatment-related immunopathological signatures in children with COVID-19 (n=105) and MIS-C (n=76). pCOVID-19 was characterized by enhanced type I IFN responses, and MIS-C by type II IFN- and NF-κB dependent responses, matrisome activation, and increased levels of Spike protein. Reduced levels of IL-33 in pCOVID-19, and of CCL22 in MIS-C suggested suppression of Th2 responses. Expansion of TRBV11-2 T-cell clonotypes in MIS-C was associated with inflammation and signatures of T-cell activation, and was reversed by glucocorticoids. The association of MIS-C with the combination of HLA A*02, B*35, C*04 alleles suggests genetic susceptibility. MIS-C B cells showed higher mutation load. Use of IVIG was identified as a confounding factor in the interpretation of autoantibody levels.

scholarly journals Type II NKT cell–mediated anergy induction in type I NKT cells prevents inflammatory liver disease

2007 ◽  
Vol 117 (8) ◽  
pp. 2302-2312 ◽  
Author(s):  
Ramesh C. Halder ◽  
Carlos Aguilera ◽  
Igor Maricic ◽  
Vipin Kumar
Keyword(s):  
Liver Disease ◽  
Nkt Cells ◽  
Type I ◽  
Type Ii ◽  
Nkt Cell
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