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1.
Nat Immunol ; 24(4): 652-663, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36807641

RESUMEN

Genetic susceptibility to type 1 diabetes is associated with homozygous expression of major histocompatibility complex class II alleles that carry specific beta chain polymorphisms. Why heterozygous expression of these major histocompatibility complex class II alleles does not confer a similar predisposition is unresolved. Using a nonobese diabetic mouse model, here we show that heterozygous expression of the type 1 diabetes-protective allele I-Ag7 ß56P/57D induces negative selection to the I-Ag7-restricted T cell repertoire, including beta-islet-specific CD4+ T cells. Surprisingly, negative selection occurs despite I-Ag7 ß56P/57D having a reduced ability to present beta-islet antigens to CD4+ T cells. Peripheral manifestations of non-cognate negative selection include a near complete loss of beta-islet-specific CXCR6+ CD4+ T cells, an inability to cross-prime islet-specific glucose-6-phosphatase catalytic subunit-related protein and insulin-specific CD8+ T cells and disease arrest at the insulitis stage. These data reveal that negative selection on non-cognate self-antigens in the thymus can promote T cell tolerance and protection from autoimmunity.


Asunto(s)
Diabetes Mellitus Tipo 1 , Ratones , Animales , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Antígenos de Histocompatibilidad Clase II , Insulina/metabolismo , Ratones Endogámicos NOD
2.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31209405

RESUMEN

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.


Asunto(s)
Autoantígenos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/citología , Animales , Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Línea Celular , Femenino , Factores de Transcripción Forkhead/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Desiminasas de la Arginina Proteica/metabolismo , Linfocitos T Reguladores/inmunología , Timo/citología
3.
Nat Immunol ; 17(8): 946-55, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27348411

RESUMEN

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.


Asunto(s)
Autoinmunidad , Regiones Determinantes de Complementariedad/genética , Diabetes Mellitus Tipo 1/inmunología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Reguladores/fisiología , Animales , Autoantígenos/inmunología , Autoantígenos/metabolismo , Diferenciación Celular , Tolerancia Central , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados
4.
Nat Immunol ; 17(9): 1093-101, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-27478940

RESUMEN

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.


Asunto(s)
Colitis/inmunología , Ganglios Linfáticos/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Síndrome Debilitante/inmunología , Animales , Autoantígenos/inmunología , Autoinmunidad , Diferenciación Celular , Proliferación Celular , Células Cultivadas , Selección Clonal Mediada por Antígenos , Modelos Animales de Enfermedad , Femenino , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteína Relacionada con TNFR Inducida por Glucocorticoide/metabolismo , Homeostasis , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/trasplante , Linfocitos T Reguladores/trasplante
5.
Nat Immunol ; 11(3): 225-31, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20139986

RESUMEN

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.


Asunto(s)
Autoantígenos/inmunología , Cromogranina A/inmunología , Diabetes Mellitus Tipo 1/inmunología , Células Secretoras de Insulina/inmunología , Fragmentos de Péptidos/inmunología , Secuencias de Aminoácidos , Secuencia de Aminoácidos , Animales , Epítopos/inmunología , Antígenos HLA-A , Espectrometría de Masas , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Datos de Secuencia Molecular
6.
Blood ; 131(21): 2335-2344, 2018 05 24.
Artículo en Inglés | MEDLINE | ID: mdl-29653965

RESUMEN

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.


Asunto(s)
Complejo CD3/genética , Inmunomodulación , Mutación , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Biomarcadores , Complejo CD3/metabolismo , Expresión Génica , Humanos , Inmunofenotipificación , Activación de Linfocitos/inmunología , Complejos Multiproteicos/metabolismo , Unión Proteica , Receptores de Antígenos de Linfocitos T/metabolismo
7.
Immunity ; 35(5): 694-704, 2011 Nov 23.
Artículo en Inglés | MEDLINE | ID: mdl-22101158

RESUMEN

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.


Asunto(s)
Antígenos de Histocompatibilidad/química , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Animales , Reacciones Cruzadas/inmunología , Ligandos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Moleculares , Péptidos/química , Péptidos/inmunología , Péptidos/metabolismo , Unión Proteica/inmunología , Conformación Proteica , Receptores de Antígenos de Linfocitos T alfa-beta/química , Linfocitos T/inmunología , Linfocitos T/metabolismo , Timo/inmunología , Timo/metabolismo
8.
Trends Immunol ; 35(6): 231-2, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24820694

RESUMEN

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.


Asunto(s)
Péptidos/química , Receptores de Antígenos de Linfocitos T/química , Linfocitos T/inmunología , Animales , Humanos
10.
J Immunol ; 192(12): 6071-82, 2014 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-24813203

RESUMEN

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.


Asunto(s)
Regiones Determinantes de Complementariedad/inmunología , Antígenos de Histocompatibilidad/inmunología , Péptidos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Linfocitos T/inmunología , Animales , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/genética , Antígenos de Histocompatibilidad/química , Antígenos de Histocompatibilidad/genética , Ratones , Ratones Noqueados , Péptidos/química , Péptidos/genética , Receptores de Antígenos de Linfocitos T alfa-beta/química , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Linfocitos T/química
11.
Cytometry A ; 97(11): 1102-1104, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32573091
12.
Proc Natl Acad Sci U S A ; 107(24): 10978-83, 2010 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-20534455

RESUMEN

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.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Insulina/inmunología , Secuencia de Aminoácidos , Animales , Presentación de Antígeno , Sitios de Unión , Cisteína/química , Epítopos/química , Epítopos/metabolismo , Hibridomas/inmunología , Insulina/química , Insulina/genética , Insulina/metabolismo , Ratones , Ratones Endogámicos NOD , Modelos Moleculares , Datos de Secuencia Molecular , Unión Proteica
14.
Diabetes Metab Res Rev ; 27(8): 784-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-22069260

RESUMEN

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.


Asunto(s)
Antígenos de Histocompatibilidad Clase II/inmunología , Insulina/genética , Fragmentos de Péptidos/genética , Animales , Autoantígenos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/prevención & control , Femenino , Antígenos HLA-DQ/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Insulina/inmunología , Ratones , Ratones Endogámicos NOD , Fragmentos de Péptidos/inmunología
15.
Elife ; 92020 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-32065580

RESUMEN

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.


Asunto(s)
Dermatitis Atópica/prevención & control , Interleucina-17/biosíntesis , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T/metabolismo , Animales , Animales Recién Nacidos , Autoantígenos/genética , Diferenciación Celular , Dermatitis Atópica/genética , Dermatitis Atópica/inmunología , Modelos Animales de Enfermedad , Expresión Génica , Interleucinas/biosíntesis , Queratinocitos/citología , Queratinocitos/metabolismo , Activación de Linfocitos , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Piel/metabolismo , Piel/microbiología , Linfocitos T/inmunología , Interleucina-22
16.
J Clin Invest ; 126(6): 2040-2, 2016 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-27183386

RESUMEN

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.


Asunto(s)
Diabetes Mellitus Tipo 1 , Linfocitos T/citología , Enfermedad Injerto contra Huésped/inmunología , Humanos , Péptidos/química , Receptores de Antígenos de Linfocitos T/química
17.
Front Immunol ; 3: 64, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-22566945

RESUMEN

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.

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