Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 61
Filtrar
1.
Nat Immunol ; 20(3): 373, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30728493

RESUMO

In the version of this article initially published, three authors (Hui-Fern Kuoy, Adam P. Uldrich and Dale. I. Godfrey) and their affiliations, acknowledgments and contributions were not included. The correct information is as follows:Ayano C. Kohlgruber1,2, Shani T. Gal-Oz3, Nelson M. LaMarche1,2, Moto Shimazaki1, Danielle Duquette4, Hui-Fern Koay5,6, Hung N. Nguyen1, Amir I. Mina4, Tyler Paras1, Ali Tavakkoli7, Ulrich von Andrian2,8, Adam P. Uldrich5,6, Dale I. Godfrey5,6, Alexander S. Banks4, Tal Shay3, Michael B. Brenner1,10* and Lydia Lynch1,4,9,10*1Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA, USA. 2Division of Medical Sciences, Harvard Medical School, Boston, MA, USA. 3Department of Life Sciences, Ben-Gurion University of the Negev, Beersheba, Israel. 4Division of Endocrinology, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. 5Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Australia. 6ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, Australia. 7Department of General and Gastrointestinal Surgery, Brigham and Women's Hospital, Boston, MA, USA. 8Department of Microbiology and Immunology, Harvard Medical School, Boston, MA, USA. 9School of Biochemistry and Immunology, Trinity College, Dublin, Ireland. 10These authors jointly supervised this work: Michael B. Brenner, Lydia Lynch. *e-mail: mbrenner@research.bwh.harvard.edu; llynch@bwh.harvard.eduAcknowledgementsWe thank A.T. Chicoine, flow cytometry core manager at the Human Immunology Center at BWH, for flow cytometry sorting. We thank D. Sant'Angelo (Rutgers Cancer Institute) for providing Zbtb16-/- mice and R. O'Brien (National Jewish Health) for providing Vg4/6-/- mice. Supported by NIH grant R01 AI11304603 (to M.B.B.), ERC Starting Grant 679173 (to L.L.), the National Health and Medical Research Council of Australia (1013667), an Australian Research Council Future Fellowship (FT140100278 for A.P.U.) and a National Health and Medical Research Council of Australia Senior Principal Research Fellowship (1117766 for D.I.G.).Author contributionsA.C.K., L.L., and M.B.B. conceived and designed the experiments, and wrote the manuscript. A.C.K., N.M.L., L.L., H.N.N., M.S., T.P., and D.D. performed the experiments. S.T.G.-O. and T.S. performed the RNA-seq analysis. A.S.B. and A.I.M. provided advice and performed the CLAMS experiments. A.T. provided human bariatric patient samples. Parabiosis experiments were performed in the laboratory of U.v.A. H.-F.K., A.P.U. and D.I.G provided critical insight into the TCR chain usage of PLZF+ γδ T cells. M.B.B., N.M.L., and L.L. critically reviewed the manuscript.The errors have been corrected in the HTML and PDF version of the article.Correction to: Nature Immunology doi:10.1038/s41590-018-0094-2 (2018), published online 18 April 2018.

2.
Nat Immunol ; 19(5): 464-474, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29670241

RESUMO

γδ T cells are situated at barrier sites and guard the body from infection and damage. However, little is known about their roles outside of host defense in nonbarrier tissues. Here, we characterize a highly enriched tissue-resident population of γδ T cells in adipose tissue that regulate age-dependent regulatory T cell (Treg) expansion and control core body temperature in response to environmental fluctuations. Mechanistically, innate PLZF+ γδ T cells produced tumor necrosis factor and interleukin (IL) 17 A and determined PDGFRα+ and Pdpn+ stromal-cell production of IL-33 in adipose tissue. Mice lacking γδ T cells or IL-17A exhibited decreases in both ST2+ Treg cells and IL-33 abundance in visceral adipose tissue. Remarkably, these mice also lacked the ability to regulate core body temperature at thermoneutrality and after cold challenge. Together, these findings uncover important physiological roles for resident γδ T cells in adipose tissue immune homeostasis and body-temperature control.


Assuntos
Tecido Adiposo/citologia , Homeostase/fisiologia , Interleucina-17/metabolismo , Linfócitos T Reguladores/fisiologia , Termogênese/fisiologia , Tecido Adiposo/fisiologia , Animais , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T gama-delta , Subpopulações de Linfócitos T/fisiologia
3.
Nat Immunol ; 19(4): 397-406, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29531339

RESUMO

The hallmark function of αß T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen-presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.


Assuntos
Antígenos CD1/imunologia , Autoantígenos/imunologia , Autoimunidade/imunologia , Glicoproteínas/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Apresentação de Antígeno/imunologia , Humanos , Lipídeos/imunologia , Ativação Linfocitária/imunologia
4.
Nat Immunol ; 17(11): 1300-1311, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27668799

RESUMO

Mucosal-associated invariant T cells (MAIT cells) detect microbial vitamin B2 derivatives presented by the antigen-presenting molecule MR1. Here we defined three developmental stages and checkpoints for the MAIT cell lineage in humans and mice. Stage 1 and stage 2 MAIT cells predominated in thymus, while stage 3 cells progressively increased in abundance extrathymically. Transition through each checkpoint was regulated by MR1, whereas the final checkpoint that generated mature functional MAIT cells was controlled by multiple factors, including the transcription factor PLZF and microbial colonization. Furthermore, stage 3 MAIT cell populations were expanded in mice deficient in the antigen-presenting molecule CD1d, suggestive of a niche shared by MAIT cells and natural killer T cells (NKT cells). Accordingly, this study maps the developmental pathway and checkpoints that control the generation of functional MAIT cells.


Assuntos
Diferenciação Celular/imunologia , Células T Invariantes Associadas à Mucosa/citologia , Células T Invariantes Associadas à Mucosa/fisiologia , Timo/imunologia , Timo/metabolismo , Animais , Antígenos CD1d/genética , Biomarcadores , Diferenciação Celular/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Imunofenotipagem , Células Progenitoras Linfoides/imunologia , Células Progenitoras Linfoides/metabolismo , Masculino , Camundongos , Camundongos Knockout , MicroRNAs/genética
5.
Nat Immunol ; 16(11): 1114-23, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26482978

RESUMO

While most studies of T lymphocytes have focused on T cells reactive to complexes of peptide and major histocompatibility complex (MHC) proteins, many other types of T cells do not fit this paradigm. These include CD1-restricted T cells, MR1-restricted mucosal associated invariant T cells (MAIT cells), MHC class Ib-reactive T cells, and γδ T cells. Collectively, these T cells are considered 'unconventional', in part because they can recognize lipids, small-molecule metabolites and specially modified peptides. Unlike MHC-reactive T cells, these apparently disparate T cell types generally show simplified patterns of T cell antigen receptor (TCR) expression, rapid effector responses and 'public' antigen specificities. Here we review evidence showing that unconventional T cells are an abundant component of the human immune system and discuss the immunotherapeutic potential of these cells and their antigenic targets.


Assuntos
Subpopulações de Linfócitos T/imunologia , Animais , Apresentação de Antígeno , Antígenos CD1/química , Antígenos CD1/metabolismo , Antígenos de Histocompatibilidade Classe I/química , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Camundongos , Modelos Imunológicos , Estrutura Molecular , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo
6.
Nat Immunol ; 16(3): 258-66, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25642819

RESUMO

A central paradigm in αß T cell-mediated immunity is the simultaneous co-recognition of antigens and antigen-presenting molecules by the αß T cell antigen receptor (TCR). CD1a presents a broad repertoire of lipid-based antigens. We found that a prototypical autoreactive TCR bound CD1a when it was presenting a series of permissive endogenous ligands, while other lipid ligands were nonpermissive to TCR binding. The structures of two TCR-CD1a-lipid complexes showed that the TCR docked over the A' roof of CD1a in a manner that precluded direct contact with permissive ligands. Nonpermissive ligands indirectly inhibited TCR binding by disrupting the TCR-CD1a contact zone. The exclusive recognition of CD1a by the TCR represents a previously unknown mechanism whereby αß T cells indirectly sense self antigens that are bound to an antigen-presenting molecule.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1/imunologia , Autoantígenos/imunologia , Lipídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Linhagem Celular , Linhagem Celular Tumoral , Células HEK293 , Humanos , Células Jurkat , Ligantes , Ligação Proteica
7.
Nat Immunol ; 16(11): 1153-61, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26437244

RESUMO

Central to adaptive immunity is the interaction between the αß T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR α-chain and ß-chain are overlaid with the α-chain and ß-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.


Assuntos
Autoantígenos/metabolismo , Complexo Principal de Histocompatibilidade/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Imunidade Adaptativa , Apresentação de Antígeno , Autoantígenos/química , Autoantígenos/genética , Células Cultivadas , Antígeno HLA-DR4/química , Antígeno HLA-DR4/genética , Antígeno HLA-DR4/metabolismo , Antígenos de Histocompatibilidade Classe II/química , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Complexo Principal de Histocompatibilidade/genética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Proinsulina/química , Proinsulina/genética , Proinsulina/imunologia , Domínios e Motivos de Interação entre Proteínas , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T Reguladores/imunologia
8.
Immunity ; 48(3): 453-473, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29562195

RESUMO

Most studies on the immunotherapeutic potential of T cells have focused on CD8 and CD4 T cells that recognize peptide antigens (Ag) presented by polymorphic major histocompatibility complex (MHC) class I and MHC class II molecules, respectively. However, unconventional T cells, which interact with MHC class Ib and MHC-I like molecules, are also implicated in tumor immunity, although their role therein is unclear. These include unconventional T cells targeting MHC class Ib molecules such as HLA-E and its murine ortholog Qa-1b, natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδ T cells. Here, we review the current understanding of the roles of these unconventional T cells in tumor immunity and discuss why further studies into the immunotherapeutic potential of these cells is warranted.


Assuntos
Imunoterapia , Terapia de Alvo Molecular , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Estudos Clínicos como Assunto , Terapia Combinada , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antígenos de Histocompatibilidade/imunologia , Antígenos de Histocompatibilidade/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias/metabolismo , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/efeitos dos fármacos , Resultado do Tratamento
9.
Nat Immunol ; 14(11): 1137-45, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24076636

RESUMO

The T cell repertoire comprises αß and γδ T cell lineages. Although it is established how αß T cell antigen receptors (TCRs) interact with antigen presented by antigen-presenting molecules, this is unknown for γδ TCRs. We describe a population of human Vδ1(+) γδ T cells that exhibit autoreactivity to CD1d and provide a molecular basis for how a γδ TCR binds CD1d-α-galactosylceramide (α-GalCer). The γδ TCR docked orthogonally, over the A' pocket of CD1d, in which the Vδ1-chain, and in particular the germ line-encoded CDR1δ loop, dominated interactions with CD1d. The TCR γ-chain sat peripherally to the interface, with the CDR3γ loop representing the principal determinant for α-GalCer specificity. Accordingly, we provide insight into how a γδ TCR binds specifically to a lipid-loaded antigen-presenting molecule.


Assuntos
Antígenos CD1d/química , Galactosilceramidas/química , Simulação de Acoplamento Molecular , Receptores de Antígenos de Linfócitos T gama-delta/química , Subpopulações de Linfócitos T/imunologia , Sequência de Aminoácidos , Antígenos CD1d/imunologia , Sítios de Ligação , Bases de Dados de Proteínas , Galactosilceramidas/imunologia , Humanos , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Subpopulações de Linfócitos T/citologia
10.
Immunity ; 44(1): 32-45, 2016 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-26795251

RESUMO

A characteristic of mucosal-associated invariant T (MAIT) cells is the expression of TRAV1-2(+) T cell receptors (TCRs) that are activated by riboflavin metabolite-based antigens (Ag) presented by the MHC-I related molecule, MR1. Whether the MR1-restricted T cell repertoire and associated Ag responsiveness extends beyond these cells remains unclear. Here, we describe MR1 autoreactivity and folate-derivative reactivity in a discrete subset of TRAV1-2(+) MAIT cells. This recognition was attributable to CDR3ß loop-mediated effects within a consensus TRAV1-2(+) TCR-MR1-Ag footprint. Furthermore, we have demonstrated differential folate- and riboflavin-derivative reactivity by a diverse population of "atypical" TRAV1-2(-) MR1-restricted T cells. We have shown that TRAV1-2(-) T cells are phenotypically heterogeneous and largely distinct from TRAV1-2(+) MAIT cells. A TRAV1-2(-) TCR docks more centrally on MR1, thereby adopting a markedly different molecular footprint to the TRAV1-2(+) TCR. Accordingly, diversity within the MR1-restricted T cell repertoire leads to differing MR1-restricted Ag specificity.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Ativação Linfocitária/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T/imunologia , Autoimunidade/imunologia , Cristalografia por Raios X , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe I/química , Humanos , Imunidade nas Mucosas/imunologia , Células Jurkat , Antígenos de Histocompatibilidade Menor , Receptores de Antígenos de Linfócitos T/química , Ressonância de Plasmônio de Superfície
11.
Eur J Immunol ; 53(6): e2250220, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36946072

RESUMO

Vγ9Vδ2 T cells can recognize various molecules associated with cellular stress or transformation, providing a unique avenue for the treatment of cancers or infectious diseases. Nonetheless, Vγ9Vδ2 T-cell-based immunotherapies frequently achieve suboptimal efficacies in vivo. Enhancing the cytotoxic effector function of Vγ9Vδ2 T cells is one potential avenue through which the immunotherapeutic potential of this subset may be improved. We compared the use of four pro-inflammatory cytokines on the effector phenotype and functions of in vitro expanded Vγ9Vδ2 T cells, and demonstrated TCR-independent cytotoxicity mediated through CD26, CD16, and NKG2D, which could be further enhanced by IL-23, IL-18, and IL-15 stimulation throughout expansion. This work defines promising culture conditions that could improve Vγ9Vδ2 T-cell-based immunotherapies and furthers our understanding of how this subset might recognize and target transformed or infected cells.


Assuntos
Receptores de Antígenos , Linfócitos T , Humanos , Citocinas/metabolismo , Receptores de Antígenos/imunologia , Proliferação de Células , Linfócitos T/citologia , Linfócitos T/metabolismo
12.
Nat Immunol ; 13(9): 857-63, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22820603

RESUMO

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 TCRß 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.


Assuntos
Antígenos CD1d/imunologia , Células Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/química , Sulfoglicoesfingolipídeos/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Antígenos CD1d/química , Cristalização , Células Matadoras Naturais/química , Ativação Linfocitária , Camundongos , Reação em Cadeia da Polimerase , Estrutura Quaternária de Proteína , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Sulfoglicoesfingolipídeos/química , Ressonância de Plasmônio de Superfície , Subpopulações de Linfócitos T/química
13.
Trends Immunol ; 42(8): 670-680, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34253468

RESUMO

Vγ9Vδ2+ T cells form part of the innate immune repertoire and are activated by phosphorylated antigens produced by many bacteria and tumors. They have long been suggested as promising targets for anti-tumor therapies, but clinical trials so far have not shown major successes. Several recent discoveries could help to overcome these shortfalls, such as those leading to an improved understanding of the role of butyrophilin molecules BTN2A1 and BTN3A1, in Vγ9Vδ2+ T cell activation. Moreover, we propose that studies suggesting the presence of live bacteria in a variety of tumors (tumor microbiome), indicate that the latter might be harnessed as a source of high affinity bacterial phosphoantigen to trigger or enhance anti-tumor immune responses.


Assuntos
Neoplasias , Receptores de Antígenos de Linfócitos T gama-delta , Antígenos CD , Butirofilinas , Imunoterapia , Ativação Linfocitária , Neoplasias/terapia
14.
Proc Natl Acad Sci U S A ; 118(34)2021 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-34417291

RESUMO

Natural killer T (NKT) cells detect lipids presented by CD1d. Most studies focus on type I NKT cells that express semi-invariant αß 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 αßTCRs 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.


Assuntos
Antígenos CD1d/metabolismo , Sulfonatos de Arila/imunologia , Autoantígenos/metabolismo , Benzofuranos/imunologia , Lipídeos/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Apresentação de Antígeno/imunologia , Antígenos CD1d/imunologia , Autoantígenos/imunologia , Humanos , Receptores de Antígenos de Linfócitos T/imunologia , Subpopulações de Linfócitos T/imunologia
15.
Immunol Rev ; 298(1): 74-83, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33017054

RESUMO

Gamma-delta (γδ) T cells are an important component of the immune system. They are often enriched in non-lymphoid tissues and exhibit diverse functional attributes including rapid activation, cytokine production, proliferation, and acquisition of cytotoxicity following both TCR-dependent and TCR-independent stimulation, but poor capacity for immunological memory. They can detect a broad range of antigens, although typically not peptide-MHC complexes in contrast to alpha-beta (αß) T cells. In humans, a prominent population of γδ T cells, defined as Vγ9Vδ2+ cells, reacts to small phosphorylated non-peptide "phosphoantigens" (pAgs). The molecular mechanism underpinning this recognition is poorly defined, but is known to involve butyrophilin family members and appears to involve indirect pAg recognition via alterations to butyrophilin molecular complexes. In this review, we discuss recent advances in our understanding of pAg recognition by γδ T cells including the role of butyrophilins and in particular, a newly described role for butyrophilin 2A1.


Assuntos
Ativação Linfocitária , Receptores de Antígenos de Linfócitos T gama-delta , Antígenos CD , Butirofilinas , Humanos , Linfócitos T
18.
Nat Immunol ; 12(9): 827-33, 2011 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-21804559

RESUMO

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 ß-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 ß-linked agonists ß-galactosylceramide (ß-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 ß-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 ß-linked self ligands to resemble the conformation of foreign α-linked ligands, which shows that induced-fit molecular mimicry can underpin the self-reactivity of NKT cell TCRs to ß-linked antigens.


Assuntos
Antígenos CD1d/imunologia , Autoimunidade , Galactosilceramidas/imunologia , Globosídeos/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta , Triexosilceramidas/imunologia , Sequência de Aminoácidos , Animais , Antígenos CD1d/química , Antígenos CD1d/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Citometria de Fluxo , Galactosilceramidas/química , Galactosilceramidas/metabolismo , Globosídeos/química , Globosídeos/metabolismo , Humanos , Hibridomas , Cinética , Camundongos , Modelos Moleculares , Mimetismo Molecular , Dados de Sequência Molecular , Células T Matadoras Naturais/citologia , Células T Matadoras Naturais/metabolismo , Ligação Proteica/imunologia , Engenharia de Proteínas/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Triexosilceramidas/química , Triexosilceramidas/metabolismo
19.
Nat Immunol ; 12(7): 616-23, 2011 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-21666690

RESUMO

Type I natural killer T cells (NKT cells) are characterized by an invariant variable region 14-joining region 18 (V(α)14-J(α)18) T cell antigen receptor (TCR) α-chain and recognition of the glycolipid α-galactosylceramide (α-GalCer) restricted to the antigen-presenting molecule CD1d. Here we describe a population of α-GalCer-reactive NKT cells that expressed a canonical V(α)10-J(α)50 TCR α-chain, which showed a preference for α-glucosylceramide (α-GlcCer) and bacterial α-glucuronic acid-containing glycolipid antigens. Structurally, despite very limited TCRα sequence identity, the V(α)10 TCR-CD1d-α-GlcCer complex had a docking mode similar to that of type I TCR-CD1d-α-GalCer complexes, although differences at the antigen-binding interface accounted for the altered antigen specificity. Our findings provide new insight into the structural basis and evolution of glycolipid antigen recognition and have notable implications for the scope and immunological role of glycolipid-specific T cell responses.


Assuntos
Galactosilceramidas/imunologia , Células T Matadoras Naturais/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Adjuvantes Imunológicos/farmacologia , Sequência de Aminoácidos , Animais , Antígenos de Bactérias/imunologia , Antígenos CD1d/imunologia , Linhagem Celular , Galactosilceramidas/farmacologia , Glucuronatos/imunologia , Humanos , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Receptores de Antígenos de Linfócitos T alfa-beta/genética
20.
Semin Cell Dev Biol ; 84: 42-47, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29183709

RESUMO

Studies of lipid reactive CD1d-restricted T cells have focussed on α-galactosylceramide reactive semi-invariant Type I NKT cells, which influence a broad range of immune responses. Much less is known about other CD1d-restricted T cells with respect to TCR diversity, function, the types of antigens they recognize and how they specifically recognize antigens presented by CD1d. In this review, we reflect on recent literature that highlights unexpected complexity within the pool of CD1d-restricted T cells and emphasize how TCR diversity greatly broadens the scope of antigen recognition.


Assuntos
Apresentação de Antígeno/imunologia , Antígenos CD1d/imunologia , Células Matadoras Naturais/citologia , Células T Matadoras Naturais/citologia , Receptores de Antígenos de Linfócitos T/imunologia , Animais , Galactosilceramidas/imunologia , Humanos , Células Matadoras Naturais/imunologia
SELEÇÃO DE REFERÊNCIAS
Detalhe da pesquisa