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1.
Elife ; 92020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32065580

RESUMO

Atopic Dermatitis (AD) is a T cell-mediated chronic skin disease and is associated with altered skin barrier integrity. Infants with mutations in genes involved in tissue barrier fitness are predisposed towards inflammatory diseases, but most do not develop or sustain the diseases, suggesting that there exist regulatory immune mechanisms to prevent aberrant inflammation. The absence of one single murine dermal cell type, the innate neonatal-derived IL-17 producing γδ T (Tγδ17) cells, from birth resulted in spontaneous, highly penetrant AD with many of the major hallmarks of human AD. In Tγδ17 cell-deficient mice, basal keratinocyte transcriptome was altered months in advance of AD induction. Tγδ17 cells respond to skin commensal bacteria and the fulminant disease in their absence was driven by skin commensal bacteria dysbiosis. AD in this model was characterized by highly expanded dermal αß T clonotypes that produce the type three cytokines, IL-17 and IL-22. These results demonstrate that neonatal Tγδ17 cells are innate skin regulatory T cells that are critical for skin homeostasis, and that IL-17 has dual homeostatic and inflammatory function in the skin.

2.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209405

RESUMO

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.


Assuntos
Autoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Desiminases de Arginina em Proteínas/metabolismo , Linfócitos T Reguladores/imunologia , Timo/citologia
3.
Blood ; 131(21): 2335-2344, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29653965

RESUMO

Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.


Assuntos
Complexo CD3/genética , Imunomodulação , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Biomarcadores , Complexo CD3/metabolismo , Expressão Gênica , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismo
5.
Nat Immunol ; 17(9): 1093-101, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27478940

RESUMO

The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper> T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities.


Assuntos
Colite/imunologia , Linfonodos/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Síndrome de Emaciação/imunologia , Animais , Autoantígenos/imunologia , Autoimunidade , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Seleção Clonal Mediada por Antígeno , Modelos Animais de Doenças , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Homeostase , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/metabolismo , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/transplante , Linfócitos T Reguladores/transplante
6.
Nat Immunol ; 17(8): 946-55, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27348411

RESUMO

Studies of individual T cell antigen receptors (TCRs) have shed some light on structural features that underlie self-reactivity. However, the general rules that can be used to predict whether TCRs are self-reactive have not been fully elucidated. Here we found that the interfacial hydrophobicity of amino acids at positions 6 and 7 of the complementarity-determining region CDR3ß robustly promoted the development of self-reactive TCRs. This property was found irrespective of the member of the ß-chain variable region (Vß) family present in the TCR or the length of the CDR3ß. An index based on these findings distinguished Vß2(+), Vß6(+) and Vß8.2(+) regulatory T cells from conventional T cells and also distinguished CD4(+) T cells selected by the major histocompatibility complex (MHC) class II molecule I-A(g7) (associated with the development of type 1 diabetes in NOD mice) from those selected by a non-autoimmunity-promoting MHC class II molecule I-A(b). Our results provide a means for distinguishing normal T cell repertoires versus autoimmunity-prone T cell repertoires.


Assuntos
Autoimunidade , Regiões Determinantes de Complementaridade/genética , Diabetes Mellitus Tipo 1/imunologia , Subpopulações de Linfócitos T/fisiologia , Linfócitos T Reguladores/fisiologia , Animais , Autoantígenos/imunologia , Autoantígenos/metabolismo , Diferenciação Celular , Tolerância Central , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout
7.
J Clin Invest ; 126(6): 2040-2, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27183386

RESUMO

The ability of a single T cell antigen receptor (TCR) to cross-react with multiple antigens allows the finite number of T cells within an organism to respond to the compendium of pathogen challenges faced during a lifetime. Effective immune surveillance, however, comes at a price. TCR cross-reactivity can allow molecular mimics to spuriously activate autoimmune T cells; it also underlies T cell rejection of organ transplants and drives graft-versus-host disease. In this issue of the JCI, Cole and colleagues provide insight into how an insulin-reactive T cell cross-reacts with pathogen-derived antigens by focusing on a limited portion of the peptides to provide a hotspot for binding. These findings dovetail with recent studies of alloreactive and autoimmune TCRs and suggest that the biochemical principles that govern conventional protein-protein interactions may allow the specificity and cross-reactivity profiles of T cells to be predicted.


Assuntos
Diabetes Mellitus Tipo 1 , Linfócitos T/citologia , Doença Enxerto-Hospedeiro/imunologia , Humanos , Peptídeos/química , Receptores de Antígenos de Linfócitos T/química
8.
Trends Immunol ; 35(6): 231-2, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24820694

RESUMO

Human genetic and environmental factors underlie susceptibility to the T cell-mediated autoimmune disease, multiple sclerosis (MS). How the environment influences the pathogenesis of MS has been difficult to parse. A recent paper in Cell shows that environmental antigens that activate myelin-specific T cells can be identified with unprecedented accuracy.


Assuntos
Peptídeos/química , Receptores de Antígenos de Linfócitos T/química , Linfócitos T/imunologia , Animais , Humanos
9.
J Immunol ; 192(12): 6071-82, 2014 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-24813203

RESUMO

The mature T cell repertoire has the ability to orchestrate immunity to a wide range of potential pathogen challenges. This ability stems from thymic development producing individual T cell clonotypes that express TCRs with unique patterns of Ag reactivity. The Ag specificity of TCRs is created from the combinatorial pairing of one of a set of germline encoded TCR Vα and Vß gene segments with randomly created CDR3 sequences. How the amalgamation of germline encoded and randomly created TCR sequences results in Ag receptors with unique patterns of ligand specificity is not fully understood. Using cellular, biophysical, and structural analyses, we show that CDR3α residues can modulate the geometry in which TCRs bind peptide-MHC (pMHC), governing whether and how germline encoded TCR Vα and Vß residues interact with MHC. In addition, a CDR1α residue that is positioned distal to the TCR-pMHC binding interface is shown to contribute to the peptide specificity of T cells. These findings demonstrate that the specificity of individual T cell clonotypes arises not only from TCR residues that create direct contacts with the pMHC, but also from a collection of indirect effects that modulate how TCR residues are used to bind pMHC.


Assuntos
Regiões Determinantes de Complementaridade/imunologia , Antígenos de Histocompatibilidade/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Linfócitos T/imunologia , Animais , Regiões Determinantes de Complementaridade/química , Regiões Determinantes de Complementaridade/genética , Antígenos de Histocompatibilidade/química , Antígenos de Histocompatibilidade/genética , Camundongos , Camundongos Knockout , Peptídeos/química , Peptídeos/genética , Receptores de Antígenos de Linfócitos T alfa-beta/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/química
11.
Front Immunol ; 3: 64, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22566945

RESUMO

A growing body of evidence suggests that autoreactive CD8 T cells contribute to the disease process in multiple sclerosis (MS). Lymphocytes in MS plaques are biased toward the CD8 lineage, and MS patients harbor CD8 T cells specific for multiple central nervous system (CNS) antigens. Currently, there are relatively few experimental model systems available to study these pathogenic CD8 T cells in vivo. However, the few studies that have been done characterizing the mechanisms used by CD8 T cells to induce CNS autoimmunity indicate that several of the paradigms of how CD4 T cells mediate CNS autoimmunity do not hold true for CD8 T cells or for patients with MS. Thus, myelin-specific CD4 T cells are likely to be one of several important mechanisms that drive CNS disease in MS patients. The focus of this review is to highlight the current models of pathogenic CNS-reactive CD8 T cells and the molecular mechanisms these lymphocytes use when causing CNS inflammation and damage. Understanding how CNS-reactive CD8 T cells escape tolerance induction and induce CNS autoimmunity is critical to our ability to propose and test new therapies for MS.

12.
Immunity ; 35(5): 694-704, 2011 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-22101158

RESUMO

A limited set of T cell receptor (TCR) variable (V) gene segments are used to create a repertoire of TCRs that recognize all major histocompatibility complex (MHC) ligands within a species. How individual αßTCRs are constructed to specifically recognize a limited set of MHC ligands is unclear. Here we have identified a role for the differential pairing of particular V gene segments in creating TCRs that recognized MHC class II ligands exclusively, or cross-reacted with classical and nonclassical MHC class I ligands. Biophysical and structural experiments indicated that TCR specificity for MHC ligands is not driven by germline-encoded pairwise interactions.Rather, identical TCRß chains can have altered peptide-MHC (pMHC) binding modes when paired with different TCRα chains. The ability of TCR chain pairing to modify how V region residues interact with pMHC helps to explain how the same V genes are used to create TCRs specific for unique MHC ligands.


Assuntos
Antígenos de Histocompatibilidade/química , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Animais , Reações Cruzadas/imunologia , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação Proteica/imunologia , Conformação Proteica , Receptores de Antígenos de Linfócitos T alfa-beta/química , Linfócitos T/imunologia , Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo
13.
Diabetes Metab Res Rev ; 27(8): 784-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22069260

RESUMO

BACKGROUND: Mutating the insulin B:9-23 peptide prevents diabetes in NOD mice. Thus, the trimolecular complex of I-Ag7-insulin B:9-23 peptide-TCR may be essential for the development of spontaneous diabetes. Pathogenic T cells recognize the B:9-23 peptide presented by I-Ag7 in what is termed register 3, with the B22 basic amino acid (arginine) of the peptide bound in pocket 9 of I-Ag7. Our hypothesis is that immunization with an insulin B:12-22 peptide linked to I-Ag7 in register 3 (I-Ag7-B:RE#3 complex) can induce specific antibodies to the complex, block pathogenic TCRs, and thus prevent diabetes. METHODS: We immunized young NOD mice with recombinant I-Ag7-B:RE#3 protein, in which two amino acids of the peptide were mutated to fix the peptide in register 3, and investigated the induced antibodies targeted to the peptide in register 3. RESULTS: Specific antibodies targeting I-Ag7-B:RE#3 but not I-Ag7-HEL were identified in the sera of I-Ag7-B:RE#3 immunized mice. The sera inhibited B:9-23-induced T-cell responses in vitro. I-Ag7-B:RE#3 immunization delayed progression to diabetes (versus PBS, p=0.0005), while immunization with I-Ag7-HEL control complex did not. CONCLUSIONS: Immunization with I-Ag7-B:RE#3 complex significantly delays the development of insulin autoantibodies and the onset of diabetes in NOD mice, which is associated with the induction of I-Ag7-B:RE#3 antibodies.


Assuntos
Antígenos de Histocompatibilidade Classe II/imunologia , Insulina/genética , Fragmentos de Peptídeos/genética , Animais , Autoantígenos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Feminino , Antígenos HLA-DQ/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Insulina/imunologia , Camundongos , Camundongos Endogâmicos NOD , Fragmentos de Peptídeos/imunologia
14.
Proc Natl Acad Sci U S A ; 107(24): 10978-83, 2010 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-20534455

RESUMO

A peptide derived from the insulin B chain contains a major epitope for diabetogenic CD4(+) T cells in the NOD mouse model of type 1 diabetes (T1D). This peptide can fill the binding groove of the NOD MHCII molecule, IA(g7), in a number of ways or "registers." We show here that a diverse set of NOD anti-insulin T cells all recognize this peptide bound in the same register. Surprisingly, this register results in the poorest binding of peptide to IA(g7). The poor binding is due to an incompatibility between the p9 amino acid of the peptide and the unique IA(g7) p9 pocket polymorphisms that are strongly associated with susceptibility to T1D. Our findings suggest that the association of autoimmunity with particular MHCII alleles may be do to poorer, rather than more favorable, binding of the critical self-epitopes, allowing T-cell escape from thymic deletion.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Insulina/imunologia , Sequência de Aminoácidos , Animais , Apresentação do Antígeno , Sítios de Ligação , Cisteína/química , Epitopos/química , Epitopos/metabolismo , Hibridomas/imunologia , Insulina/química , Insulina/genética , Insulina/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Modelos Moleculares , Dados de Sequência Molecular , Ligação Proteica
15.
Nat Immunol ; 11(3): 225-31, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20139986

RESUMO

Autoreactive CD4(+) T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4(+) T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-A(g7) in an atypical manner, occupying only the carboxy-terminal half of the I-A(g7) peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.


Assuntos
Autoantígenos/imunologia , Cromogranina A/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Fragmentos de Peptídeos/imunologia , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Epitopos/imunologia , Antígenos HLA-A , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Dados de Sequência Molecular
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