NF-κB1 deficiency stimulates the progression of non-alcoholic steatohepatitis (NASH) in mice by promoting NKT-cell-mediated responses

2012 ◽  
Vol 124 (4) ◽  
pp. 279-287 ◽  
Author(s):  
Irene Locatelli ◽  
Salvatore Sutti ◽  
Marco Vacchiano ◽  
Cristina Bozzola ◽  
Emanuele Albano
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nkt Cells ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Type I ◽  
Nkt Cell ◽  
Deficient Diet ◽  
Cell Recruitment ◽  
Chemokine Ligand

Growing evidence indicates that NF-κB (nuclear factor κB) activation contributes to the pathogenesis of NASH (non-alcoholic steatohepatisis). Among the NF-κB subunits, p50/NF-κB1 has regulatory activities down-modulating NF-κB-mediated responses. In the present study, we investigated the effects of NF-κB1 deficiency on the progression of NASH induced by feeding mice on an MCD (methionine/choline-deficient) diet. Following 4 weeks on the MCD diet, steatosis, ALT (alanine aminotransferase) release, hepatocyte apoptosis, lobular inflammation and TNFα (tumour necrosis factor α) production were higher in NF-κB1−/− (NF-κB1-knockout) mice than in WT (wild-type) mice. NF-κB1−/− mice also showed appreciable centrilobular collagen deposition, an increased number of activated hepatic stellate cells and higher type-I procollagen-α and TIMP-1 (tissue inhibitor of metalloproteases-1) mRNA expression. Although NF-κB p50 homodimers regulate macrophage activation, the number of hepatic macrophages and liver mRNAs for iNOS (inducible NO synthase), IL (interleukin)-12p40, CCL2 (CC chemokine ligand 2) and CXCL10 (CXC chemokine ligand 10) were comparable in the two strains. NASH was associated with an increase in liver infiltrating T-cells that was more evident in MCD-fed NF-κB1−/− than in similarly treated WT mice. Flow cytorimetry showed that T-cell recruitment involved effector CD8+ T-cells without changes in the helper CD4+ T-cell fraction. Furthermore, although NASH lowered hepatic NKT cells [NK (natural killer) T-cells] in WT mice, the NKT cell pool was selectively increased in the livers of MCD-fed NF-κB1−/− mice. Such NKT cell recruitment was associated with an early overexpression of IL-15, a cytokine controlling NKT cell survival and maturation. In the livers of MCD-fed NF-κB1−/− mice, but not in those of WT littermates, we also observed an up-regulation in the production of NKT-related cytokines IFN (interferon)-γ and osteopontin. Taken together, these results indicate that NF-κB1 down-modulation enhanced NASH progression to fibrosis by favouring NKT cell recruitment, stressing the contribution of NKT cells in the pathogenesis of NASH.

scholarly journals m6A demethylase ALKBH5 controls CD4+ T cell pathogenicity and promotes autoimmunity

2021 ◽  
Vol 7 (25) ◽  
pp. eabg0470
Author(s):  
Jing Zhou ◽  
Xingli Zhang ◽  
Jiajia Hu ◽  
Rihao Qu ◽  
Zhibin Yu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Messenger Rna ◽  
Interferon Γ ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Chemokine Ligand ◽  
The Central Nervous System ◽  
Chemokine Ligand 2

N6-methyladenosine (m6A) modification is dynamically regulated by “writer” and “eraser” enzymes. m6A “writers” have been shown to ensure the homeostasis of CD4+ T cells, but the “erasers” functioning in T cells is poorly understood. Here, we reported that m6A eraser AlkB homolog 5 (ALKBH5), but not FTO, maintains the ability of naïve CD4+ T cells to induce adoptive transfer colitis. In addition, T cell–specific ablation of ALKBH5 confers protection against experimental autoimmune encephalomyelitis. During the induced neuroinflammation, ALKBH5 deficiency increased m6A modification on interferon-γ and C-X-C motif chemokine ligand 2 messenger RNA (mRNA), thus decreasing their mRNA stability and protein expression in CD4+ T cells. These modifications resulted in attenuated CD4+ T cell responses and diminished recruitment of neutrophils into the central nervous system. Our findings reveal an unexpected specific role of ALKBH5 as an m6A eraser in controlling the pathogenicity of CD4+ T cells during autoimmunity.

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.

scholarly journals The Molecular Adapter Carma1 Controls Entry of IκB Kinase into the Central Immune Synapse

2004 ◽  
Vol 200 (9) ◽  
pp. 1167-1177 ◽  
Author(s):  
Hiromitsu Hara ◽  
Christopher Bakal ◽  
Teiji Wada ◽  
Denis Bouchard ◽  
Robert Rottapel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Nuclear Factor Κb ◽  
Interferon Γ ◽  
Lymphocyte Function ◽  
Specific System ◽  
Immune Synapse ◽  
Iκb Kinase

Carma1 (also known as caspase recruitment domain [CARD]11, Bimp3) is a CARD-containing membrane-associated guanylate kinase family protein that plays an essential role in antigen receptor–induced nuclear factor κB activation. We investigated the role of Carma1 in the assembly of signaling molecules at the immune synapse using a peptide-specific system. We report that Carma1 is essential for peptide-induced interleukin 2 and interferon γ production, but dispensable for proliferation in T cells. Recruitment and distribution of T cell receptor, lymphocyte function associated 1, lipid rafts, and protein kinase C (PKC)θ to central and peripheral immune synapse regions occur normally in Carma1−/− T cells. Carma1 controls entry of IκB kinase (IKK) into lipid raft aggregates and the central region of the immune synapse, as well as activation of IKK downstream of PKC. Our data provide the first genetic evidence on a new class of molecular scaffold that controls entry of defined signaling components, IKK, into the central supramolecular activation cluster at T cell–antigen-presenting cell interfaces without having any apparent effect on the overall organization and formation of immune synapses.

scholarly journals TIM-3 blockade enhances IL-12-dependent antitumor immunity by promoting CD8+ T cell and XCR1+ dendritic cell spatial co-localization

2022 ◽  
Vol 10 (1) ◽  
pp. e003571
Author(s):  
Alycia Gardner ◽  
Álvaro de Mingo Pulido ◽  
Kay Hänggi ◽  
Sarah Bazargan ◽  
Alexis Onimus ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interferon Γ ◽  
Response To Therapy ◽  
Interleukin 12 ◽  
Type I ◽  
T Cell Infiltration ◽  
Blocking Antibodies ◽  
Bone Marrow Chimeras

BackgroundT cell immunoglobulin and mucin domain containing−3 (TIM-3) blocking antibodies are currently being evaluated in clinical trials for solid and hematological malignancies. Despite its identification on T cells, TIM-3 is predominantly expressed by myeloid cells, including XCR1+ type I conventional dendritic cells (cDC1s). We have recently shown that TIM-3 blockade promotes expression of CXCR3 chemokine ligands by tumor cDCs, but how this drives a CD8+ T cell-dependent response to therapy is unclear.MethodsT cell infiltration, effector function, and spatial localization in relation to XCR1+ cDC1s were evaluated in a murine orthotopic mammary carcinoma model during response to TIM-3 blockade and paclitaxel chemotherapy. Mixed bone marrow chimeras and diphtheria toxin depletion were used to determine the role of specific genes in cDC1s during therapeutic responses.ResultsTIM-3 blockade increased interferon-γ expression by CD8+ T cells without altering immune infiltration. cDC1 expression of CXCL9, but not CXCL10, was required for response to TIM-3 blockade. CXCL9 was also necessary for the increased proximity observed between CD8+ T cells and XCR1+ cDC1s during therapy. Tumor responses were dependent on cDC1 expression of interleukin-12, but not MHCI.ConclusionsTIM-3 blockade increases exposure of intratumoral CD8+ T cells to cDC1-derived cytokines, with implications for the design of therapeutic strategies using antibodies against TIM-3.

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 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 The molecular bases of δ/αβ T cell–mediated antigen recognition

2014 ◽  
Vol 211 (13) ◽  
pp. 2599-2615 ◽  
Author(s):  
Daniel G. Pellicci ◽  
Adam P. Uldrich ◽  
Jérôme Le Nours ◽  
Fiona Ross ◽  
Eric Chabrol ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Nkt Cells ◽  
Type I ◽  
Human Immune System ◽  
Human T Cells ◽  
Molecular Bases ◽  
Αβ T Cells

αβ and γδ T cells are disparate T cell lineages that can respond to distinct antigens (Ags) via the use of the αβ and γδ T cell Ag receptors (TCRs), respectively. Here we characterize a population of human T cells, which we term δ/αβ T cells, expressing TCRs comprised of a TCR-δ variable gene (Vδ1) fused to joining α and constant α domains, paired with an array of TCR-β chains. We demonstrate that these cells, which represent ∼50% of all Vδ1+ human T cells, can recognize peptide- and lipid-based Ags presented by human leukocyte antigen (HLA) and CD1d, respectively. Similar to type I natural killer T (NKT) cells, CD1d-lipid Ag-reactive δ/αβ T cells recognized α-galactosylceramide (α-GalCer); however, their fine specificity for other lipid Ags presented by CD1d, such as α-glucosylceramide, was distinct from type I NKT cells. Thus, δ/αβTCRs contribute new patterns of Ag specificity to the human immune system. Furthermore, we provide the molecular bases of how δ/αβTCRs bind to their targets, with the Vδ1-encoded region providing a major contribution to δ/αβTCR binding. Our findings highlight how components from αβ and γδTCR gene loci can recombine to confer Ag specificity, thus expanding our understanding of T cell biology and TCR diversity.

scholarly journals Distinct Functional Lineages of Human Vα24 Natural Killer T Cells

2002 ◽  
Vol 195 (5) ◽  
pp. 637-641 ◽  
Author(s):  
Peter T. Lee ◽  
Kamel Benlagha ◽  
Luc Teyton ◽  
Albert Bendelac
Keyword(s):  
T Cells ◽  
Natural Killer ◽  
Chemokine Receptors ◽  
Type I Diabetes ◽  
Cell Receptor ◽  
Nkt Cells ◽  
Peripheral Blood Lymphocytes ◽  
Cytokine Secretion ◽  
Type I ◽  
Nkt Cell

CD1d-restricted autoreactive natural killer (NK)T cells have been reported to regulate a range of disease conditions, including type I diabetes and immune rejection of cancer, through the secretion of either T helper (Th)2 or Th1 cytokines. However, mechanisms underlying Th2 versus Th1 cytokine secretion by these cells are not well understood. Since most healthy subjects express &lt;1 NKT cell per 1,000 peripheral blood lymphocytes (PBLs), we devised a new method based on the combined used of T cell receptor (TCR)-specific reagents α-galactosylceramide (αGalCer) loaded CD1d-tetramers and anti-Vα24 monoclonal antibody, to specifically identify and characterize these rare cells in fresh PBLs. We report here that CD4+ and CD4−CD8− (double negative [DN]) NKT cell subsets represent functionally distinct lineages with marked differences in their profile of cytokine secretion and pattern of expression of chemokine receptors, integrins, and NK receptors. CD4+ NKT cells were the exclusive producers of interleukin (IL)-4 and IL-13 upon primary stimulation, whereas DN NKT cells had a strict Th1 profile and prominently expressed several NK lineage receptors. These findings may explain how NKT cells could promote Th2 responses in some conditions and Th1 in others, and should be taken into consideration for intervention in relevant diseases.

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 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.

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