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1.
Cell ; 186(3): 607-620.e17, 2023 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-36640762

RESUMO

Tissue immunity and responses to injury depend on the coordinated action and communication among physiological systems. Here, we show that, upon injury, adaptive responses to the microbiota directly promote sensory neuron regeneration. At homeostasis, tissue-resident commensal-specific T cells colocalize with sensory nerve fibers within the dermis, express a transcriptional program associated with neuronal interaction and repair, and promote axon growth and local nerve regeneration following injury. Mechanistically, our data reveal that the cytokine interleukin-17A (IL-17A) released by commensal-specific Th17 cells upon injury directly signals to sensory neurons via IL-17 receptor A, the transcription of which is specifically upregulated in injured neurons. Collectively, our work reveals that in the context of tissue damage, preemptive immunity to the microbiota can rapidly bridge biological systems by directly promoting neuronal repair, while also identifying IL-17A as a major determinant of this fundamental process.


Assuntos
Interleucina-17 , Microbiota , Regeneração Nervosa , Células Th17 , Axônios , Regeneração Nervosa/fisiologia , Células Receptoras Sensoriais , Animais , Camundongos , Células Th17/citologia
2.
Cell ; 172(4): 784-796.e18, 2018 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-29358051

RESUMO

Mammalian barrier surfaces are constitutively colonized by numerous microorganisms. We explored how the microbiota was sensed by the immune system and the defining properties of such responses. Here, we show that a skin commensal can induce T cell responses in a manner that is restricted to non-classical MHC class I molecules. These responses are uncoupled from inflammation and highly distinct from pathogen-induced cells. Commensal-specific T cells express a defined gene signature that is characterized by expression of effector genes together with immunoregulatory and tissue-repair signatures. As such, non-classical MHCI-restricted commensal-specific immune responses not only promoted protection to pathogens, but also accelerated skin wound closure. Thus, the microbiota can induce a highly physiological and pleiotropic form of adaptive immunity that couples antimicrobial function with tissue repair. Our work also reveals that non-classical MHC class I molecules, an evolutionarily ancient arm of the immune system, can promote homeostatic immunity to the microbiota.


Assuntos
Imunidade Adaptativa , Bactérias/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Microbiota/imunologia , Pele/imunologia , Linfócitos T/imunologia , Animais , Regulação da Expressão Gênica/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Camundongos , Camundongos Transgênicos
3.
Immunity ; 54(8): 1745-1757.e7, 2021 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-34348118

RESUMO

Environmental enteric dysfunction (EED) is a gastrointestinal inflammatory disease caused by malnutrition and chronic infection. EED is associated with stunting in children and reduced efficacy of oral vaccines. To study the mechanisms of oral vaccine failure during EED, we developed a microbiota- and diet-dependent mouse EED model. Analysis of E. coli-labile toxin vaccine-specific CD4+ T cells in these mice revealed impaired CD4+ T cell responses in the small intestine and but not the lymph nodes. EED mice exhibited increased frequencies of small intestine-resident RORγT+FOXP3+ regulatory T (Treg) cells. Targeted deletion of RORγT from Treg cells restored small intestinal vaccine-specific CD4 T cell responses and vaccine-mediated protection upon challenge. However, ablation of RORγT+FOXP3+ Treg cells made mice more susceptible to EED-induced stunting. Our findings provide insight into the poor efficacy of oral vaccines in EED and highlight how RORγT+FOXP3+ Treg cells can regulate intestinal immunity while leaving systemic responses intact.


Assuntos
Toxinas Bacterianas/imunologia , Vacinas contra Escherichia coli/imunologia , Gastroenteropatias/imunologia , Intestino Delgado/imunologia , Linfócitos T Reguladores/imunologia , Administração Oral , Animais , Linhagem Celular , Modelos Animais de Doenças , Drosophila , Escherichia coli/imunologia , Feminino , Fatores de Transcrição Forkhead/metabolismo , Gastroenteropatias/microbiologia , Gastroenteropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Vacinação
4.
Nat Immunol ; 17(2): 187-95, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26726812

RESUMO

Studies of repertoires of mouse monoclonal CD4(+) T cells have revealed several mechanisms of self-tolerance; however, which mechanisms operate in normal repertoires is unclear. Here we studied polyclonal CD4(+) T cells specific for green fluorescent protein expressed in various organs, which allowed us to determine the effects of specific expression patterns on the same epitope-specific T cells. Peptides presented uniformly by thymic antigen-presenting cells were tolerated by clonal deletion, whereas peptides excluded from the thymus were ignored. Peptides with limited thymic expression induced partial clonal deletion and impaired effector T cell potential but enhanced regulatory T cell potential. These mechanisms were also active for T cell populations specific for endogenously expressed self antigens. Thus, the immunotolerance of polyclonal CD4(+) T cells was maintained by distinct mechanisms, according to self-peptide expression patterns.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Expressão Gênica , Tolerância Imunológica , Peptídeos/genética , Peptídeos/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Autoantígenos/química , Autoantígenos/genética , Autoantígenos/imunologia , Autoimunidade , Deleção Clonal/genética , Deleção Clonal/imunologia , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/imunologia , Feminino , Genes Reporter , Camundongos , Camundongos Transgênicos , Peptídeos/química , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timo/imunologia , Timo/metabolismo
5.
Nat Immunol ; 17(3): 304-14, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26829766

RESUMO

The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation.


Assuntos
Autoimunidade/imunologia , Diferenciação Celular/imunologia , Anergia Clonal/imunologia , Histocompatibilidade Materno-Fetal/imunologia , Tolerância Periférica/imunologia , Células Precursoras de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Artrite Experimental/imunologia , Linfócitos T CD4-Positivos/imunologia , Proliferação de Células , Citocinas/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Genes Codificadores da Cadeia alfa de Receptores de Linfócitos T , Immunoblotting , Masculino , Camundongos , Camundongos Knockout , Neuropilina-1/metabolismo , Gravidez , Receptores de Antígenos de Linfócitos T/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tolerância a Antígenos Próprios , Timócitos/imunologia
6.
Cell ; 153(4): 785-96, 2013 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-23663778

RESUMO

A naive CD4(+) T cell population specific for a microbial peptide:major histocompatibility complex II ligand (p:MHCII) typically consists of about 100 cells, each with a different T cell receptor (TCR). Following infection, this population produces a consistent ratio of effector cells that activate microbicidal functions of macrophages or help B cells make antibodies. We studied the mechanism that underlies this division of labor by tracking the progeny of single naive T cells. Different naive cells produced distinct ratios of macrophage and B cell helpers but yielded the characteristic ratio when averaged together. The effector cell pattern produced by a given naive cell correlated with the TCR-p:MHCII dwell time or the amount of p:MHCII. Thus, the consistent production of effector cell subsets by a polyclonal population of naive cells results from averaging the diverse behaviors of individual clones, which are instructed in part by the strength of TCR signaling.


Assuntos
Infecções Bacterianas/imunologia , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Receptores de Antígenos de Linfócitos T/metabolismo , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos de Histocompatibilidade Classe II/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia
7.
Proc Natl Acad Sci U S A ; 117(28): 16465-16474, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601220

RESUMO

Under steady-state conditions, the immune system is poised to sense and respond to the microbiota. As such, immunity to the microbiota, including T cell responses, is expected to precede any inflammatory trigger. How this pool of preformed microbiota-specific T cells contributes to tissue pathologies remains unclear. Here, using an experimental model of psoriasis, we show that recall responses to commensal skin fungi can significantly aggravate tissue inflammation. Enhanced pathology caused by fungi preexposure depends on Th17 responses and neutrophil extracellular traps and recapitulates features of the transcriptional landscape of human lesional psoriatic skin. Together, our results propose that recall responses directed to skin fungi can directly promote skin inflammation and that exploration of tissue inflammation should be assessed in the context of recall responses to the microbiota.


Assuntos
Arthrodermataceae/fisiologia , Microbiota , Psoríase/imunologia , Pele/microbiologia , Animais , Arthrodermataceae/classificação , Arthrodermataceae/genética , Arthrodermataceae/isolamento & purificação , Armadilhas Extracelulares/imunologia , Armadilhas Extracelulares/microbiologia , Feminino , Humanos , Imunidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Psoríase/microbiologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Simbiose , Células Th17/imunologia
8.
Nat Immunol ; 11(1): 83-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19935657

RESUMO

We used a sensitive method based on tetramers of peptide and major histocompatibility complex II (pMHCII) to determine whether CD4(+) memory T cells resemble the T helper type 1 (T(H)1) and interleukin 17 (IL-17)-producing T helper (T(H)17) subsets described in vitro. Intravenous or intranasal infection with Listeria monocytogenes induced pMHCII-specific CD4(+) naive T cells to proliferate and produce effector cells, about 10% of which resembled T(H)1 or T(H)17 cells, respectively. T(H)1 cells were also present among the memory cells that survived 3 months after infection, whereas T(H)17 cells disappeared. The short lifespan of T(H)17 cells was associated with small amounts of the antiapoptotic protein Bcl-2, the IL-15 receptor and the receptor CD27, and little homeostatic proliferation. These results suggest that T(H)1 cells induced by intravenous infection are more efficient at entering the memory pool than are T(H)17 cells induced by intranasal infection.


Assuntos
Interleucina-17/imunologia , Listeriose/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th1/imunologia , Sequência de Aminoácidos , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Diferenciação Celular/imunologia , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/imunologia , Células Clonais/imunologia , Células Clonais/patologia , Citometria de Fluxo , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Interações Hospedeiro-Patógeno/imunologia , Memória Imunológica/imunologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Listeria monocytogenes/genética , Listeria monocytogenes/fisiologia , Listeriose/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptores de Interleucina-15/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Auxiliares-Indutores/patologia , Células Th1/metabolismo , Células Th1/patologia , Fatores de Tempo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Proc Natl Acad Sci U S A ; 116(47): 23643-23652, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31672911

RESUMO

The cross-talk between the microbiota and the immune system plays a fundamental role in the control of host physiology. However, the tissue-specific factors controlling this dialogue remain poorly understood. Here we demonstrate that T cell responses to commensal colonization are associated with the development of organized cellular clusters within the skin epithelium. These organized lymphocyte clusters are surrounded by keratinocytes expressing a discrete program associated with antigen presentation and antimicrobial defense. Notably, IL-22-mediated keratinocyte-intrinsic MHC class II expression was required for the selective accumulation of commensal-induced IFN-γ, but not IL-17A-producing CD4+ T cells within the skin. Taking these data together, this work uncovers an unexpected role for MHC class II expression by keratinocytes in the control of homeostatic type 1 responses to the microbiota. Our findings have important implications for the understanding of the tissue-specific rules governing the dialogue between a host and its microbiota.


Assuntos
Epiderme/microbiologia , Antígenos de Histocompatibilidade Classe II/biossíntese , Interações entre Hospedeiro e Microrganismos/imunologia , Queratinócitos/imunologia , Microbiota/imunologia , Células Th1/imunologia , Animais , Apresentação de Antígeno , Candida albicans/imunologia , Epiderme/imunologia , Genes MHC da Classe II , Interferon gama/biossíntese , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Especificidade de Órgãos , Quimera por Radiação , Organismos Livres de Patógenos Específicos , Staphylococcus aureus/imunologia , Staphylococcus epidermidis/imunologia , Simbiose , Células Th1/metabolismo
10.
Nature ; 520(7545): 104-8, 2015 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-25539086

RESUMO

The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Pele/imunologia , Pele/microbiologia , Simbiose/imunologia , Animais , Antígenos de Bactérias/imunologia , Linfócitos T CD8-Positivos/citologia , Células Dendríticas/citologia , Humanos , Imunidade Inata/imunologia , Interleucina-17/imunologia , Células de Langerhans/citologia , Células de Langerhans/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Primatas , Pele/citologia , Staphylococcus epidermidis/imunologia
12.
Nature ; 510(7503): 152-6, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-24739972

RESUMO

T-helper-17 (TH17) cells have critical roles in mucosal defence and in autoimmune disease pathogenesis. They are most abundant in the small intestine lamina propria, where their presence requires colonization of mice with microbiota. Segmented filamentous bacteria (SFB) are sufficient to induce TH17 cells and to promote TH17-dependent autoimmune disease in animal models. However, the specificity of TH17 cells, the mechanism of their induction by distinct bacteria, and the means by which they foster tissue-specific inflammation remain unknown. Here we show that the T-cell antigen receptor (TCR) repertoire of intestinal TH17 cells in SFB-colonized mice has minimal overlap with that of other intestinal CD4(+) T cells and that most TH17 cells, but not other T cells, recognize antigens encoded by SFB. T cells with antigen receptors specific for SFB-encoded peptides differentiated into RORγt-expressing TH17 cells, even if SFB-colonized mice also harboured a strong TH1 cell inducer, Listeria monocytogenes, in their intestine. The match of T-cell effector function with antigen specificity is thus determined by the type of bacteria that produce the antigen. These findings have significant implications for understanding how commensal microbiota contribute to organ-specific autoimmunity and for developing novel mucosal vaccines.


Assuntos
Antígenos de Bactérias/imunologia , Bactérias Gram-Positivas/imunologia , Intestinos/imunologia , Simbiose , Células Th17/imunologia , Animais , Antígenos de Bactérias/química , Vacinas Bacterianas , Diferenciação Celular , Epitopos de Linfócito T/química , Epitopos de Linfócito T/imunologia , Bactérias Gram-Positivas/química , Hibridomas/imunologia , Imunidade nas Mucosas/imunologia , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Intestino Delgado/citologia , Intestino Delgado/imunologia , Intestinos/citologia , Listeria monocytogenes/imunologia , Camundongos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Células Th17/citologia
13.
Proc Natl Acad Sci U S A ; 112(41): 12782-7, 2015 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-26417101

RESUMO

Intranasal (i.n.) infections preferentially generate Th17 cells. We explored the basis for this anatomic preference by tracking polyclonal CD4(+) T cells specific for an MHC class II-bound peptide from the mucosal pathogen Streptococcus pyogenes. S. pyogenes MHC class II-bound peptide-specific CD4(+) T cells were first activated in the cervical lymph nodes following i.n. inoculation and then differentiated into Th17 cells. S. pyogenes-induced Th17 formation depended on TGF-ß1 from dendritic cells and IL-6 from a CD301b(+) dendritic cell subset located in the cervical lymph nodes but not the spleen. Thus, the tendency of i.n. infection to induce Th17 cells is related to cytokine production by specialized dendritic cells that drain this site.


Assuntos
Células Dendríticas/imunologia , Interleucina-6/imunologia , Lectinas Tipo C/imunologia , Doenças Nasais/imunologia , Infecções Estreptocócicas/imunologia , Streptococcus pyogenes/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta1/imunologia , Animais , Células Dendríticas/patologia , Imunidade Celular , Camundongos , Doenças Nasais/microbiologia , Doenças Nasais/patologia , Infecções Estreptocócicas/patologia , Células Th17/patologia
14.
Proc Natl Acad Sci U S A ; 111(23): 8577-82, 2014 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-24843166

RESUMO

Immune responses can make protein therapeutics ineffective or even dangerous. We describe a general computational protein design method for reducing immunogenicity by eliminating known and predicted T-cell epitopes and maximizing the content of human peptide sequences without disrupting protein structure and function. We show that the method recapitulates previous experimental results on immunogenicity reduction, and we use it to disrupt T-cell epitopes in GFP and Pseudomonas exotoxin A without disrupting function.


Assuntos
Epitopos de Linfócito T/imunologia , Imunotoxinas/imunologia , Engenharia de Proteínas/métodos , Proteínas/imunologia , ADP Ribose Transferases/química , ADP Ribose Transferases/genética , ADP Ribose Transferases/imunologia , Animais , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Toxinas Bacterianas/imunologia , Linhagem Celular Tumoral , Desenho Assistido por Computador , Epitopos de Linfócito T/genética , Exotoxinas/química , Exotoxinas/genética , Exotoxinas/imunologia , Citometria de Fluxo , Proteínas de Fluorescência Verde/química , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Antígenos HLA/genética , Antígenos HLA/imunologia , Humanos , Imunização , Imunotoxinas/química , Imunotoxinas/genética , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Dados de Sequência Molecular , Estrutura Terciária de Proteína , Proteínas/química , Proteínas/genética , Homologia de Sequência de Aminoácidos , Espectrometria de Fluorescência , Máquina de Vetores de Suporte , Fatores de Virulência/química , Fatores de Virulência/genética , Fatores de Virulência/imunologia , Exotoxina A de Pseudomonas aeruginosa
15.
J Immunol ; 191(10): 4913-7, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24123682

RESUMO

Insulin-specific CD4(+) T cells are required for type 1 diabetes. How these cells are regulated and how tolerance breaks down are poorly understood because of a lack of reagents. Therefore, we used an enrichment method and tetramer reagents to track insulin-specific CD4(+) T cells in diabetes-susceptible NOD and resistant B6 mice expressing I-A(g7). Insulin-specific cells were detected in both strains, but they only became activated, produced IFN-γ, and infiltrated the pancreas in NOD mice. Unexpectedly, the majority of Ag-experienced cells in NOD mice displayed an anergic phenotype, but this population decreased with age as tolerance was lost. B6 mice expressing I-A(g7) were protected because insulin-specific cells did not become effector or anergic T cells but remained naive. These data suggest that NOD mice promote tolerance through anergy induction, but a small proportion of autoreactive T cells escape anergy to provoke type 1 diabetes.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Anergia Clonal/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 1/imunologia , Animais , Insulina/imunologia , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/citologia , Pâncreas/imunologia
16.
ACS Med Chem Lett ; 15(9): 1606-1614, 2024 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-39291002

RESUMO

Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong in vitro augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 µM), a favorable in vitro safety profile, and good projected human pharmacokinetics.

17.
PLoS Pathog ; 7(9): e1002252, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21966268

RESUMO

Group A streptococcus (GAS, Streptococcus pyogenes) is the cause of a variety of clinical conditions, ranging from pharyngitis to autoimmune disease. Peptide-major histocompatibility complex class II (pMHCII) tetramers have recently emerged as a highly sensitive means to quantify pMHCII-specific CD4+ helper T cells and evaluate their contribution to both protective immunity and autoimmune complications induced by specific bacterial pathogens. In lieu of identifying an immunodominant peptide expressed by GAS, a surrogate peptide (2W) was fused to the highly expressed M1 protein on the surface of GAS to allow in-depth analysis of the CD4+ helper T cell response in C57BL/6 mice that express the I-A(b) MHCII molecule. Following intranasal inoculation with GAS-2W, antigen-experienced 2W:I-A(b)-specific CD4+ T cells were identified in the nasal-associated lymphoid tissue (NALT) that produced IL-17A or IL-17A and IFN-γ if infection was recurrent. The dominant Th17 response was also dependent on the intranasal route of inoculation; intravenous or subcutaneous inoculations produced primarily IFN-γ+ 2W:I-A(b+) CD4+ T cells. The acquisition of IL-17A production by 2W:I-A(b)-specific T cells and the capacity of mice to survive infection depended on the innate cytokine IL-6. IL-6-deficient mice that survived infection became long-term carriers despite the presence of abundant IFN-γ-producing 2W:I-A(b)-specific CD4+ T cells. Our results suggest that an imbalance between IL-17- and IFN-γ-producing CD4+ T cells could contribute to GAS carriage in humans.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Interleucina-6/imunologia , Streptococcus pyogenes/imunologia , Células Th17/imunologia , Administração Intranasal , Animais , Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Proteínas de Transporte/imunologia , Interferon gama/biossíntese , Interleucina-17/biossíntese , Interleucina-6/deficiência , Tecido Linfoide/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Recombinantes de Fusão/imunologia
18.
J Exp Med ; 216(6): 1450-1464, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053612

RESUMO

CD4+ T helper 17 (Th17) cells protect vertebrate hosts from extracellular pathogens at mucosal surfaces. Th17 cells form from naive precursors when signals from the T cell antigen receptor (TCR) and certain cytokine receptors induce the expression of the RORγt transcription factor, which activates a set of Th17-specific genes. Using T cell-specific loss-of-function experiments, we find that two components of the Polycomb repressive complex 1.1 (PRC1.1), BCL6 corepressor (BCOR) and KDM2B, which helps target the complex to unmethylated CpG DNA islands, are required for optimal Th17 cell formation in mice after Streptococcus pyogenes infection. Genome-wide expression and BCOR chromatin immunoprecipitation studies revealed that BCOR directly represses Lef1, Runx2, and Dusp4, whose products inhibit Th17 differentiation. Together, the results suggest that the PRC1.1 components BCOR and KDM2B work together to enhance Th17 cell formation by repressing Th17 fate suppressors.


Assuntos
Linhagem da Célula , Proteínas Correpressoras/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Proteínas Repressoras/metabolismo , Células Th17/citologia , Células Th17/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Diferenciação Celular , Citocinas/metabolismo , Proteínas F-Box/metabolismo , Feminino , Regulação da Expressão Gênica , Histona Desmetilases com o Domínio Jumonji/metabolismo , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Streptococcus pyogenes/fisiologia
19.
Science ; 363(6422)2019 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-30523076

RESUMO

Barrier tissues are primary targets of environmental stressors and are home to the largest number of antigen-experienced lymphocytes in the body, including commensal-specific T cells. We found that skin-resident commensal-specific T cells harbor a paradoxical program characterized by a type 17 program associated with a poised type 2 state. Thus, in the context of injury and exposure to inflammatory mediators such as interleukin-18, these cells rapidly release type 2 cytokines, thereby acquiring contextual functions. Such acquisition of a type 2 effector program promotes tissue repair. Aberrant type 2 responses can also be unleashed in the context of local defects in immunoregulation. Thus, commensal-specific T cells co-opt tissue residency and cell-intrinsic flexibility as a means to promote both local immunity and tissue adaptation to injury.


Assuntos
Plasticidade Celular , Pele/lesões , Pele/microbiologia , Simbiose , Células Th17/imunologia , Células Th17/microbiologia , Ferimentos e Lesões/imunologia , Alarminas/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/microbiologia , Candida albicans , Feminino , Fator de Transcrição GATA3/metabolismo , Interleucinas/imunologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Confocal , Microscopia de Fluorescência , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Análise de Sequência de RNA , Staphylococcus epidermidis , Transcriptoma
20.
Science ; 366(6464)2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31649166

RESUMO

How early-life colonization and subsequent exposure to the microbiota affect long-term tissue immunity remains poorly understood. Here, we show that the development of mucosal-associated invariant T (MAIT) cells relies on a specific temporal window, after which MAIT cell development is permanently impaired. This imprinting depends on early-life exposure to defined microbes that synthesize riboflavin-derived antigens. In adults, cutaneous MAIT cells are a dominant population of interleukin-17A (IL-17A)-producing lymphocytes, which display a distinct transcriptional signature and can subsequently respond to skin commensals in an IL-1-, IL-18-, and antigen-dependent manner. Consequently, local activation of cutaneous MAIT cells promotes wound healing. Together, our work uncovers a privileged interaction between defined members of the microbiota and MAIT cells, which sequentially controls both tissue-imprinting and subsequent responses to injury.


Assuntos
Microbiota/imunologia , Células T Invariantes Associadas à Mucosa/citologia , Riboflavina/biossíntese , Cicatrização/imunologia , Animais , Bactérias/classificação , Bactérias/metabolismo , Vida Livre de Germes , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Interleucina-1/imunologia , Interleucina-17/imunologia , Interleucina-18/imunologia , Interleucina-23/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Antígenos de Histocompatibilidade Menor/genética , Antígenos de Histocompatibilidade Menor/imunologia , Pele/imunologia , Pele/microbiologia , Organismos Livres de Patógenos Específicos
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