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

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.

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The Role of NKT Cells in Glioblastoma

Cells ◽

10.3390/cells10071641 ◽

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.

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

10.1101/2021.03.05.433980 ◽

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

Blood ◽

10.1182/blood-2007-05-092866 ◽

2008 ◽

Vol 111 (12) ◽

pp. 5637-5645 ◽

Cited By ~ 106

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.

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

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00114.2011 ◽

2011 ◽

Vol 301 (6) ◽

pp. L975-L984 ◽

Cited By ~ 25

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.

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104420118 ◽

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.

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Faculty Opinions recommendation of Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1090008.545405 ◽

2007 ◽

Author(s):

Randy Brutkiewicz

Keyword(s):

Liver Disease ◽

Nkt Cells ◽

Type I ◽

Type Ii ◽

Nkt Cell

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Regulation of the Induction and Function of Cytotoxic T Lymphocytes by Natural Killer T Cell

Journal of Biomedicine and Biotechnology ◽

10.1155/2010/641757 ◽

2010 ◽

Vol 2010 ◽

pp. 1-8 ◽

Cited By ~ 8

Author(s):

Hiroyasu Ito ◽

Mitsuru Seishima

Keyword(s):

T Lymphocytes ◽

Natural Killer ◽

Cytotoxic T Lymphocytes ◽

Treatment Strategies ◽

Nkt Cells ◽

Host Immune System ◽

Type I ◽

Type Ii ◽

And Function ◽

Natural Killer T

Cytotoxic T lymphocytes (CTLs) play a crucial role in the infections and the antitumor immunity. Induction and activation of antigen-specific CTLs is an important strategy in immunotherapy for various diseases, and several researchers have focused on the modulation of CTL induction and function. Natural killer T (NKT) cells are an important focus area of researchers studying immunomodulatory responses to tumors and infectious diseases. CD1d-restricted NKT cells consist of type I NKT cells and type II NKT cells. -galactosylceramide (-GalCer)-activated type I NKT cells secrete both Th1 (e.g., IFN-) and Th2 cytokines, affect the expression of costimulatory molecules in immune cells, and regulate the host immune system. Type II NKT cells, however, are stimulated by sulfatide, a self-glycolipid derived from myelin, and play an immunosuppressive role in animal model of autoimmune diseases. CTL generation, activation, and suppression are strongly affected by activated type I and type II NKT cells. Thus, the regulation of these NKT cells leads to the modification of CTL function. CTLs contribute to antimicrobial responses, antitumor immune and autoimmune responses. Understanding the role of NKT cells in the regulation of CTL generation, activation, and suppression enable the development of novel treatment strategies for these diseases.

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