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1.
J Immunol ; 203(3): 639-646, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31209102

RESUMO

Signaling through CD27 plays a role in T cell activation and memory. However, it is currently unknown how this costimulatory receptor influences CD4+ effector T (Teff) cells in inflamed tissues. In the current study, we used a murine model of inducible self-antigen expression in the epidermis to elucidate the functional role of CD27 on autoreactive Teff cells. Expression of CD27 on Ag-specific Teff cells resulted in enhanced skin inflammation when compared with CD27-deficient Teff cells. CD27 signaling promoted the accumulation of IFN-γ and IL-2-producing T cells in skin draining lymph nodes in a cell-intrinsic fashion. Surprisingly, this costimulatory pathway had minimal effect on early T cell activation and proliferation. Instead, signaling through CD27 resulted in the progressive survival of Teff cells during the autoimmune response. Using BH3 profiling to assess mitochondrial cell priming, we found that CD27-deficient cells were equally as sensitive as CD27-sufficient cells to mitochondrial outer membrane polarization upon exposure to either BH3 activator or sensitizer peptides. In contrast, CD27-deficient Teff cells expressed higher levels of active caspase 8. Taken together, these results suggest that CD27 does not promote Teff cell survival by increasing expression of antiapoptotic BCL2 family members but instead acts by preferentially suppressing the cell-extrinsic apoptosis pathway, highlighting a previously unidentified role for CD27 in augmenting autoreactive Teff cell responses.

2.
Arthritis Rheumatol ; 71(3): 431-440, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30277008

RESUMO

OBJECTIVE: Adoptive Treg cell therapy has great potential to treat autoimmune disease. Currently, very little is known about how these cells impact inflamed tissues. This study was undertaken to elucidate how autologous Treg cell therapy influences tissue inflammation in human autoimmune disease. METHODS: We describe a systemic lupus erythematosus (SLE) patient with active skin disease who received adoptive Treg therapy. We comprehensively quantified Treg cells and immune activation in peripheral blood and skin, with data obtained at multiple time points posttreatment. RESULTS: Deuterium tracking of infused Treg cells revealed the transient presence of cells in peripheral blood, accompanied by increased percentages of highly activated Treg cells in diseased skin. Flow cytometric analysis and whole transcriptome RNA sequencing revealed that Treg cell accumulation in skin was associated with a marked attenuation of the interferon-γ pathway and a reciprocal augmentation of the interleukin-17 (IL-17) pathway. This phenomenon was more pronounced in skin relative to peripheral blood. To validate these findings, we investigated Treg cell adoptive transfer of skin inflammation in a murine model and found that it also resulted in a pronounced skewing away from Th1 immunity and toward IL-17 production. CONCLUSION: We report the first case of a patient with SLE treated with autologous adoptive Treg cell therapy. Taken together, our results suggest that this treatment leads to increased activated Treg cells in inflamed skin, with a dynamic shift from Th1 to Th17 responses.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Imunoterapia Adotiva/métodos , Lúpus Eritematoso Sistêmico/terapia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia
3.
Sci Immunol ; 3(30)2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30578350

RESUMO

Regulatory T cells (Tregs) are closely related to TH17 cells and use aspects of the TH17-differentiation program for optimal immune regulation. In several chronic inflammatory human diseases, Tregs express IL-17A, suggesting that dysregulation of TH17-associated pathways in Tregs may result in either loss of suppressive function and/or conversion into pathogenic cells. The pathways that regulate the TH17 program in Tregs are poorly understood. We have identified two TNF receptor superfamily (TNFRSF) members, CD27 and OX40, that are preferentially expressed by skin-resident Tregs Both CD27 and OX40 signaling suppressed the expression of TH17-associated genes from Tregs in a cell-intrinsic manner in vitro and in vivo. However, only OX40 played a nonredundant role in promoting Treg accumulation. Tregs that lacked both CD27 and OX40 were defective in controlling skin inflammation and expressed high levels of IL-17A, as well as the master TH17 transcription factor, RORγt. Last, we found that CD27 expression was inversely correlated with Treg IL-17 production in skin of patients with psoriasis and hidradenitis suppurativa. Together, our results suggest that TNFRSF members play both redundant and distinct roles in regulating Treg plasticity in tissues.


Assuntos
Glicoproteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Glicoproteínas de Membrana/deficiência , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Fatores de Necrose Tumoral/deficiência
4.
J Immunol ; 200(12): 4012-4023, 2018 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-29703862

RESUMO

Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of α and ß subunits that mediate cell-to-cell and cell-to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a ß integrin-binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin α4ß1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function.


Assuntos
Integrinas/imunologia , Tolerância Periférica/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/imunologia , Inflamação/imunologia , Camundongos , Talina/imunologia , Transcriptoma/imunologia
5.
J Immunol ; 198(12): 4639-4651, 2017 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-28515282

RESUMO

Talin, a cytoskeletal protein essential in mediating integrin activation, has been previously shown to be involved in the regulation of T cell proliferation and function. In this study, we describe a role for talin in maintaining the homeostasis and survival of the regulatory T (Treg) cell pool. T cell-specific deletion of talin in Tln1fl/flCd4Cre mice resulted in spontaneous lymphocyte activation, primarily due to numerical and functional deficiencies of Treg cells in the periphery. Peripheral talin-deficient Treg cells were unable to maintain high expression of IL-2Rα, resulting in impaired IL-2 signaling and ultimately leading to increased apoptosis through downregulation of prosurvival proteins Bcl-2 and Mcl-1. The requirement for talin in maintaining high IL-2Rα expression by Treg cells was due, in part, to integrin LFA-1-mediated interactions between Treg cells and dendritic cells. Collectively, our data suggest a critical role for talin in Treg cell-mediated maintenance of immune homeostasis.


Assuntos
Homeostase , Ativação Linfocitária , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Talina/metabolismo , Animais , Apoptose , Células Dendríticas/imunologia , Genes bcl-2 , Interleucina-2/imunologia , Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Linfócitos T Reguladores/fisiologia , Talina/deficiência , Talina/imunologia
6.
J Clin Invest ; 125(6): 2228-33, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25893595

RESUMO

Autoimmune reactions reflect an imbalance between effector and regulatory immune responses, typically develop through stages of initiation and propagation, and often show phases of resolution (indicated by clinical remissions) and exacerbations (indicated by symptomatic flares). The fundamental underlying mechanism of autoimmunity is defective elimination and/or control of self-reactive lymphocytes. Studies in humans and experimental animal models are revealing the genetic and environmental factors that contribute to autoimmunity. A major goal of research in this area is to exploit this knowledge to better understand the pathogenesis of autoimmune diseases and to develop strategies for reestablishing the normal balance between effector and regulatory immune responses.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Exposição Ambiental/efeitos adversos , Linfócitos/imunologia , Animais , Doenças Autoimunes/patologia , Humanos , Linfócitos/patologia
7.
J Immunol ; 194(5): 2249-59, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25617472

RESUMO

During an immune response against a microbial pathogen, activated naive T lymphocytes give rise to effector cells that provide acute host defense and memory cells that provide long-lived immunity. It has been shown that T lymphocytes can undergo asymmetric division, enabling the daughter cells to inherit unequal amounts of fate-determining proteins and thereby acquire distinct fates from their inception. In this study, we show that the absence of the atypical protein kinase C (PKC) isoforms, PKCζ and PKCλ/ι, disrupts asymmetric CD8(+) T lymphocyte division. These alterations were associated with aberrant acquisition of a pre-effector transcriptional program, detected by single-cell gene expression analyses, in lymphocytes that had undergone their first division in vivo and enhanced differentiation toward effector fates at the expense of memory fates. Together, these results demonstrate a role for atypical PKC in regulating asymmetric division and the specification of divergent CD8(+) T lymphocyte fates early during an immune response.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Divisão Celular/imunologia , Imunidade Inata , Isoenzimas/imunologia , Listeriose/imunologia , Proteína Quinase C/imunologia , Animais , Linfócitos T CD8-Positivos/enzimologia , Linfócitos T CD8-Positivos/microbiologia , Linfócitos T CD8-Positivos/patologia , Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/microbiologia , Células Dendríticas/patologia , Regulação da Expressão Gênica , Memória Imunológica , Isoenzimas/genética , Isoenzimas/metabolismo , Listeria monocytogenes/imunologia , Listeriose/enzimologia , Listeriose/microbiologia , Listeriose/patologia , Camundongos , Camundongos Knockout , Proteína Quinase C/genética , Proteína Quinase C/metabolismo , Transdução de Sinais , Análise de Célula Única , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/microbiologia , Subpopulações de Linfócitos T/patologia
8.
Nat Immunol ; 15(12): 1162-70, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25362490

RESUMO

MicroRNAs (miRNAs) exert powerful effects on immunological function by tuning networks of target genes that orchestrate cell activity. We sought to identify miRNAs and miRNA-regulated pathways that control the type 2 helper T cell (TH2 cell) responses that drive pathogenic inflammation in asthma. Profiling miRNA expression in human airway-infiltrating T cells revealed elevated expression of the miRNA miR-19a in asthma. Modulating miR-19 activity altered TH2 cytokine production in both human and mouse T cells, and TH2 cell responses were markedly impaired in cells lacking the entire miR-17∼92 cluster. miR-19 promoted TH2 cytokine production and amplified inflammatory signaling by direct targeting of the inositol phosphatase PTEN, the signaling inhibitor SOCS1 and the deubiquitinase A20. Thus, upregulation of miR-19a in asthma may be an indicator and a cause of increased TH2 cytokine production in the airways.


Assuntos
Asma/imunologia , Citocinas/biossíntese , MicroRNAs/imunologia , Células Th2/imunologia , Animais , Asma/genética , Asma/metabolismo , Líquido da Lavagem Broncoalveolar/citologia , Ensaios Clínicos como Assunto , Citometria de Fluxo , Ensaios de Triagem em Larga Escala , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Transgênicos , Reação em Cadeia da Polimerase Multiplex , Células Th2/metabolismo , Regulação para Cima
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