T. Mallevaey - Academia.edu (original) (raw)
Papers by T. Mallevaey
Proceedings of the National Academy of Sciences, 2013
Significance Several different populations of T lymphocytes develop in the thymus from a common p... more Significance Several different populations of T lymphocytes develop in the thymus from a common precursor. Each population plays a unique and critical role in the mounting and resolution of an immune response. The mechanisms responsible for the emergence of these different populations remain incompletely understood. We demonstrate that strict “Goldilocks” conditions of affinity for self-lipids by the T-cell antigen receptor expressed on T-cell precursors are necessary for imprinting the proper developmental program toward the invariant NK T-cell lineage. Our results establish a direct link between the affinity of the T-cell receptor for self-antigens and the proper development of a unique population of lymphocytes that has been implicated in the modulation of a multitude of immune responses in mice and humans.
Proceedings of the National Academy of Sciences, 2011
Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented... more Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented by CD1d. Although the TCR α-chain is invariant, NKT TCR Vβ exhibits greater diversity, with one (Vβ11) and three (Vβ8, Vβ7, and Vβ2) Vβ chains in humans and mice, respectively. With the exception of the Vβ2 NKT TCR, NKT TCRs possess canonical tyrosine residues within complementarity determining region (CDR) 2β that are critical for CD1d binding. Thus, how Vβ2 NKT TCR docks with CD1d-Ag was unclear. Despite the absence of the CDR2β-encoded tyrosine residues, we show that the Vβ2 NKT TCR engaged CD1d-Ag in a similar manner and with a comparable affinity and energetic footprint to the manner observed for the Vβ8.2 and Vβ7 NKT TCRs. Accordingly, the germline–encoded regions of the TCR β-chain do not exclusively dictate the innate NKT TCR-CD1d-Ag docking mode. Nevertheless, clear fine specificity differences for the CD1d-Ag existed between the Vβ2 NKT TCR and the Vβ8.2 and Vβ7 NKT TCRs, with...
Nature Immunology, 2012
Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of di... more Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRβ chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.
Nature Immunology, 2011
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids,... more The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono-and tri-glycosylated β-linked agonists βgalactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.
Immunity, 2009
Mouse type I natural killer T cell receptors (iNKT TCRs) use a single Va14-Ja18 sequence and Vbs ... more Mouse type I natural killer T cell receptors (iNKT TCRs) use a single Va14-Ja18 sequence and Vbs that are almost always Vb8.2, Vb7, or Vb2, although the basis of this differential usage is unclear. We showed that the Vb bias occurred as a consequence of the CDR2b loops determining the affinity of the iNKT TCR for CD1d-glycolipids, thus controlling positive selection. Within a conserved iNKT-TCR-CD1d docking framework, these inherent Vb-CD1d affinities are further modulated by the hypervariable CDR3b loop, thereby defining a functional interplay between the two iNKT TCR CDRb loops. These Vb biases revealed a broadly hierarchical response in which Vb8.2 > Vb7 > Vb2 in the recognition of diverse CD1d ligands. This restriction of the iNKT TCR repertoire during thymic selection paradoxically ensures that each peripheral iNKT cell recognizes a similar spectrum of antigens.
Immunity, 2011
The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and sel... more The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self-and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3b loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple selfantigens can be recognized in a similar manner by autoreactive NKT TCRs.
European Journal of Immunology, 2012
We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4 Th1 T cell cl... more We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4 Th1 T cell clones. Using multispectral flow cytometry, we showed that CD40 and CD154 are co-expressed and form complexes on the surface of activated T cells. We also demonstrate that activated T cells can transactivate CD4+CD40+ T cells through the CD40-CD154 pathway. To investigate the role of CD40 signaling on Th1 cells, we used the diabetogenic clone BDC-5.2.9 retrovirally transduced with a truncated form of the CD40 molecule to produce a CD40 dominant-negative T cell clone. Upon challenge with antigen in vitro, the production of IFN-γ by BDC-5.2.9 CD40DN was greatly reduced and in vivo, the dominant-negative variant was unable to induce diabetes. Transduction with the CD40DN vector was also effective in preventing transfer of disease by primary NOD CD4 T cells. Ex vivo analysis of pancreatic infiltrates after transfer of BDC-5.2.9 CD40DN revealed an overall reduction of cell numbers and cytokine production by both T cells and macrophages. These data indicate that CD40 is an important signaling molecule on autoreactive CD4 T cells and contributes to their pathogenic effector function.
Immunology and cell biology, 2015
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sit... more Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded p...
Nat Immunol, 2011
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids,... more The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding
Proceedings of the National Academy of Sciences, 2013
Significance Several different populations of T lymphocytes develop in the thymus from a common p... more Significance Several different populations of T lymphocytes develop in the thymus from a common precursor. Each population plays a unique and critical role in the mounting and resolution of an immune response. The mechanisms responsible for the emergence of these different populations remain incompletely understood. We demonstrate that strict “Goldilocks” conditions of affinity for self-lipids by the T-cell antigen receptor expressed on T-cell precursors are necessary for imprinting the proper developmental program toward the invariant NK T-cell lineage. Our results establish a direct link between the affinity of the T-cell receptor for self-antigens and the proper development of a unique population of lymphocytes that has been implicated in the modulation of a multitude of immune responses in mice and humans.
Proceedings of the National Academy of Sciences, 2011
Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented... more Natural killer T cell antigen receptors (NKT TCRs) recognize lipid-based antigens (Ags) presented by CD1d. Although the TCR α-chain is invariant, NKT TCR Vβ exhibits greater diversity, with one (Vβ11) and three (Vβ8, Vβ7, and Vβ2) Vβ chains in humans and mice, respectively. With the exception of the Vβ2 NKT TCR, NKT TCRs possess canonical tyrosine residues within complementarity determining region (CDR) 2β that are critical for CD1d binding. Thus, how Vβ2 NKT TCR docks with CD1d-Ag was unclear. Despite the absence of the CDR2β-encoded tyrosine residues, we show that the Vβ2 NKT TCR engaged CD1d-Ag in a similar manner and with a comparable affinity and energetic footprint to the manner observed for the Vβ8.2 and Vβ7 NKT TCRs. Accordingly, the germline–encoded regions of the TCR β-chain do not exclusively dictate the innate NKT TCR-CD1d-Ag docking mode. Nevertheless, clear fine specificity differences for the CD1d-Ag existed between the Vβ2 NKT TCR and the Vβ8.2 and Vβ7 NKT TCRs, with...
Nature Immunology, 2012
Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of di... more Natural killer T cells (NKT cells) are divided into type I and type II subsets on the basis of differences in their T cell antigen receptor (TCR) repertoire and CD1d-antigen specificity. Although the mode by which type I NKT cell TCRs recognize CD1d-antigen has been established, how type II NKT cell TCRs engage CD1d-antigen is unknown. Here we provide a basis for how a type II NKT cell TCR, XV19, recognized CD1d-sulfatide. The XV19 TCR bound orthogonally above the A' pocket of CD1d, in contrast to the parallel docking of type I NKT cell TCRs over the F' pocket of CD1d. At the XV19 TCR-CD1d-sulfatide interface, the TCRα and TCRβ chains sat centrally on CD1d, where the malleable CDR3 loops dominated interactions with CD1d-sulfatide. Accordingly, we highlight the diverse mechanisms by which NKT cell TCRs can bind CD1d and account for the distinct antigen specificity of type II NKT cells.
Nature Immunology, 2011
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids,... more The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono-and tri-glycosylated β-linked agonists βgalactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding these disparate antigens, the NKT cell TCRs docked onto CD1d similarly, achieving this by flattening the conformation of the β-linked ligands regardless of the size of the glycosyl head group. Unexpectedly, the antigenicity of iGb3 was attributable to its terminal sugar group making compensatory interactions with CD1d. Thus, the NKT cell TCR molds the β-linked self ligands to Reprints and permissions information is available online at http://www.nature.com/reprints/index.html.
Immunity, 2009
Mouse type I natural killer T cell receptors (iNKT TCRs) use a single Va14-Ja18 sequence and Vbs ... more Mouse type I natural killer T cell receptors (iNKT TCRs) use a single Va14-Ja18 sequence and Vbs that are almost always Vb8.2, Vb7, or Vb2, although the basis of this differential usage is unclear. We showed that the Vb bias occurred as a consequence of the CDR2b loops determining the affinity of the iNKT TCR for CD1d-glycolipids, thus controlling positive selection. Within a conserved iNKT-TCR-CD1d docking framework, these inherent Vb-CD1d affinities are further modulated by the hypervariable CDR3b loop, thereby defining a functional interplay between the two iNKT TCR CDRb loops. These Vb biases revealed a broadly hierarchical response in which Vb8.2 > Vb7 > Vb2 in the recognition of diverse CD1d ligands. This restriction of the iNKT TCR repertoire during thymic selection paradoxically ensures that each peripheral iNKT cell recognizes a similar spectrum of antigens.
Immunity, 2011
The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and sel... more The antigen receptor for natural killer T cells (NKT TCR) binds CD1d-restricted microbial and self-lipid antigens, although the molecular basis of self-CD1d recognition is unclear. Here, we have characterized NKT TCR recognition of CD1d molecules loaded with natural self-antigens (Ags) and report the 2.3 Å resolution structure of an autoreactive NKT TCR-phosphatidylinositol-CD1d complex. NKT TCR recognition of self-and foreign antigens was underpinned by a similar mode of germline-encoded recognition of CD1d. However, NKT TCR autoreactivity is mediated by unique sequences within the non-germline-encoded CDR3b loop encoding for a hydrophobic motif that promotes self-association with CD1d. Accordingly, NKT cell autoreactivity may arise from the inherent affinity of the interaction between CD1d and the NKT TCR, resulting in the recognition of a broad range of CD1d-restricted self-antigens. This demonstrates that multiple selfantigens can be recognized in a similar manner by autoreactive NKT TCRs.
European Journal of Immunology, 2012
We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4 Th1 T cell cl... more We have investigated the role of CD40 signaling in islet-reactive, diabetogenic CD4 Th1 T cell clones. Using multispectral flow cytometry, we showed that CD40 and CD154 are co-expressed and form complexes on the surface of activated T cells. We also demonstrate that activated T cells can transactivate CD4+CD40+ T cells through the CD40-CD154 pathway. To investigate the role of CD40 signaling on Th1 cells, we used the diabetogenic clone BDC-5.2.9 retrovirally transduced with a truncated form of the CD40 molecule to produce a CD40 dominant-negative T cell clone. Upon challenge with antigen in vitro, the production of IFN-γ by BDC-5.2.9 CD40DN was greatly reduced and in vivo, the dominant-negative variant was unable to induce diabetes. Transduction with the CD40DN vector was also effective in preventing transfer of disease by primary NOD CD4 T cells. Ex vivo analysis of pancreatic infiltrates after transfer of BDC-5.2.9 CD40DN revealed an overall reduction of cell numbers and cytokine production by both T cells and macrophages. These data indicate that CD40 is an important signaling molecule on autoreactive CD4 T cells and contributes to their pathogenic effector function.
Immunology and cell biology, 2015
Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sit... more Interleukin-17A (IL-17A) is a pro-inflammatory cytokine that has an important role at mucosal sites in a wide range of immune responses including infection, allergy and auto-immunity. γδ T cells are recognized as IL-17 producers, but based on the level of CD3 expression, we now define the remarkable ability of a CD3(bright) γδ T-cell subset with an effector memory phenotype to rapidly produce IL-17A, but not interferon-γ. CD3(bright) γδ T cells uniformly express the canonical germline encoded Vγ6/Vδ1(+) T-cell receptor. They are widely distributed with a preferential representation in the lungs and skin are negatively impacted in the absence of retinoic acid receptor-related orphan receptor gammat expression or endogenous flora. This population responded rapidly to various stimuli in a mechanism involving IL-23 and NOD-like receptor family, pyrin domain containing 3 (NLRP3)-inflammasome-dependent IL-1β. Finally, we demonstrated that IL-17-producing CD3(bright) γδ T cells responded p...
Nat Immunol, 2011
The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids,... more The most potent foreign antigens for natural killer T cells (NKT cells) are α-linked glycolipids, whereas NKT cell self-reactivity involves weaker recognition of structurally distinct β-linked glycolipid antigens. Here we provide the mechanism for the autoreactivity of T cell antigen receptors (TCRs) on NKT cells to the mono- and tri-glycosylated β-linked agonists β-galactosylceramide (β-GalCer) and isoglobotrihexosylceramide (iGb3), respectively. In binding