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1.
Nano Lett ; 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31478664

RESUMO

Activation of T cells by antigen presenting cells (APCs) initiates their proliferation, cytokine production, and killing of infected or cancerous cells. We and others have shown that T-cell receptors require mechanical forces for triggering, and these forces arise during the interaction of T cells with APCs. Efficient activation of T cells in vitro is necessary for clinical applications. In this paper, we studied the impact of combining mechanical, oscillatory movements provided by an orbital shaker with soft, biocompatible, artificial APCs (aAPCs) of various sizes and amounts of antigen. We showed that these aAPCs allow for testing the strength of signal delivered to T cells, and enabled us to confirm that that absolute amounts of antigen engaged by the T cell are more important for activation than the density of antigen. We also found that when our aAPCs interact with T cells in the context of an oscillatory mechanoenvironment, they roughly double antigenic signal strength, compared to conventional, static culture. Combining these effects, our aAPCs significantly outperformed the commonly used Dynabeads. We finally demonstrated that tuning the signal strength down to a submaximal "sweet spot" allows for robust expansion of induced regulatory T cells. In conclusion, augmenting engineered aAPCs with mechanical forces offers a novel approach for tuning of T-cell activation and differentiation.

2.
Am J Hum Genet ; 105(3): 549-561, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.

4.
Front Immunol ; 10: 753, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31031754

RESUMO

Gain-of-function variants in p110δ, the catalytic subunit of phosphatidylinositol 3-kinase (PI3K) expressed in lymphocytes, cause activated PI3-kinase δ syndrome (APDS), a primary immunodeficiency that is characterized by recurrent infections, viremia, lymphadenopathy, and autoimmunity. The mechanism of autoimmunity in APDS has not been well-understood. Here, we show the profound skewing of peripheral CD4+ T cells to a T follicular helper (TFH) phenotype in a patient with APDS bearing a novel p110δ variant, Y524S. We also saw a diminishment of transient Foxp3 expression in activated T cells. Mechanistic studies revealed that both the new variant and a previously described, pathogenic variant (E81K) enhanced an interaction between intracellular Osteopontin and p85α. This interaction had been shown in mice to promote TFH differentiation. Our results demonstrate a new influence of PI3K on human T cell differentiation that is unrelated to its lipid-kinase activity and suggest that TFH should be monitored in APDS patients.

5.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

6.
Curr Protoc Chem Biol ; 11(2): e63, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30707509

RESUMO

This manuscript details methods to ligate cell-surface receptors on live cells with precise spatiotemporal control using an atomic force microscope (AFM) to deliver ligands. This approach can be used to image cellular responses upon activating T cell receptors when the AFM is mounted on an optical microscope. Moreover, the AFM measures forces generated by the cell during the contact. Using AFM to trigger cellular responses adds an important capability to the field of mechanobiology. We describe how to incorporate anti-CD3 antibodies or other molecules onto an AFM cantilever and how to use AFM to activate T cells. © 2019 by John Wiley & Sons, Inc.

7.
Pediatrics ; 143(2)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30683812

RESUMO

OBJECTIVES: Newborn screening for severe combined immunodeficiency (SCID) was instituted in California in 2010. In the ensuing 6.5 years, 3 252 156 infants in the state had DNA from dried blood spots assayed for T-cell receptor excision circles (TRECs). Abnormal TREC results were followed-up with liquid blood testing for T-cell abnormalities. We report the performance of the SCID screening program and the outcomes of infants who were identified. METHODS: Data that were reviewed and analyzed included demographics, nursery summaries, TREC and lymphocyte flow-cytometry values, and available follow-up, including clinical and genetic diagnoses, treatments, and outcomes. RESULTS: Infants with clinically significant T-cell lymphopenia (TCL) were successfully identified at a rate of 1 in 15 300 births. Of these, 50 cases of SCID, or 1 in 65 000 births (95% confidence interval 1 in 51 000-1 in 90 000) were found. Prompt treatment led to 94% survival. Infants with non-SCID TCL were also identified, diagnosed and managed, including 4 with complete DiGeorge syndrome who received thymus transplants. Although no cases of typical SCID are known to have been missed, 2 infants with delayed-onset leaky SCID had normal neonatal TREC screens but came to clinical attention at 7 and 23 months of age. CONCLUSIONS: Population-based TREC testing, although unable to detect immune defects in which T cells are present at birth, is effective for identifying SCID and clinically important TCL with high sensitivity and specificity. The experience in California supports the rapid, widespread adoption of SCID newborn screening.

9.
Adv Mater ; 30(7)2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29315824

RESUMO

T-cell immunotherapy is a promising approach for cancer, infection, and autoimmune diseases. However, significant challenges hamper its therapeutic potential, including insufficient activation, delivery, and clonal expansion of T-cells into the tumor environment. To facilitate T-cell activation and differentiation in vitro, core-shell microparticles are developed for sustained delivery of cytokines. These particles are enriched by heparin to enable a steady release of interleukin-2 (IL-2), the major T-cell growth factor, over 10+ d. The controlled delivery of cytokines is used to steer lineage specification of cultured T-cells. This approach enables differentiation of T-cells into central memory and effector memory subsets. It is shown that the sustained release of stromal cell-derived factor 1α could accelerate T-cell migration. It is demonstrated that CD4+ T-cells could be induced to high concentrations of regulatory T-cells through controlled release of IL-2 and transforming growth factor beta. It is found that CD8+ T-cells that received IL-2 from microparticles are more likely to gain effector functions as compared with traditional administration of IL-2. Culture of T-cells within 3D scaffolds that contain IL-2-secreting microparticles enhances proliferation as compared with traditional, 2D approaches. This yield a new method to control the fate of T-cells and ultimately to new strategies for immune therapy.

10.
J Biol Chem ; 293(2): 567-578, 2018 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-29183997

RESUMO

We have identified a novel role for hyaluronan (HA), an extracellular matrix polymer, in governing the mechanical properties of inflamed tissues. We recently reported that insulitis in type 1 diabetes of mice and humans is preceded by intraislet accumulation of HA, a highly hygroscopic polymer. Using the double transgenic DO11.10 × RIPmOVA (DORmO) mouse model of type 1 diabetes, we asked whether autoimmune insulitis was associated with changes in the stiffness of islets. To measure islet stiffness, we used atomic force microscopy (AFM) and developed a novel "bed of nails"-like approach that uses quartz glass nanopillars to anchor islets, solving a long-standing problem of keeping tissue-scale objects immobilized while performing AFM. We measured stiffness via AFM nanoindentation with a spherical indenter and found that insulitis made islets mechanically soft compared with controls. Conversely, treatment with 4-methylumbelliferone, a small-molecule inhibitor of HA synthesis, reduced HA accumulation, diminished swelling, and restored basal tissue stiffness. These results indicate that HA content governs the mechanical properties of islets. In hydrogels with variable HA content, we confirmed that increased HA leads to mechanically softer hydrogels, consistent with our model. In light of recent reports that the insulin production of islets is mechanosensitive, these findings open up an exciting new avenue of research into the fundamental mechanisms by which inflammation impacts local cellular responses.


Assuntos
Ácido Hialurônico/metabolismo , Inflamação/metabolismo , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Animais , Doenças Autoimunes/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Hidrogéis , Himecromona/farmacologia , Camundongos , Microscopia de Força Atômica
11.
Biophys J ; 113(7): 1574-1584, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28978449

RESUMO

Advances in methods that determine cell mechanical phenotype, or mechanotype, have demonstrated the utility of biophysical markers in clinical and research applications ranging from cancer diagnosis to stem cell enrichment. Here, we introduce quantitative deformability cytometry (q-DC), a method for rapid, calibrated, single-cell mechanotyping. We track changes in cell shape as cells deform into microfluidic constrictions, and we calibrate the mechanical stresses using gel beads. We observe that time-dependent strain follows power-law rheology, enabling single-cell measurements of apparent elastic modulus, Ea, and power-law exponent, ß. To validate our method, we mechanotype human promyelocytic leukemia (HL-60) cells and thereby confirm q-DC measurements of Ea = 0.53 ± 0.04 kPa. We also demonstrate that q-DC is sensitive to pharmacological perturbations of the cytoskeleton as well as differences in the mechanotype of human breast cancer cell lines (Ea = 2.1 ± 0.1 and 0.80 ± 0.19 kPa for MCF-7 and MDA-MB-231 cells). To establish an operational framework for q-DC, we investigate the effects of applied stress and cell/pore-size ratio on mechanotype measurements. We show that Ea increases with applied stress, which is consistent with stress stiffening behavior of cells. We also find that Ea increases for larger cell/pore-size ratios, even when the same applied stress is maintained; these results indicate strain stiffening and/or dependence of mechanotype on deformation depth. Taken together, the calibrated measurements enabled by q-DC should advance applications of cell mechanotype in basic research and clinical settings.


Assuntos
Fenômenos Fisiológicos Celulares , Técnicas Analíticas Microfluídicas , Análise de Célula Única , Fenômenos Biomecânicos , Calibragem , Linhagem Celular Tumoral , Forma Celular , Simulação por Computador , Citoesqueleto/metabolismo , Módulo de Elasticidade , Desenho de Equipamento , Humanos , Dispositivos Lab-On-A-Chip , Técnicas Analíticas Microfluídicas/instrumentação , Técnicas Analíticas Microfluídicas/métodos , Modelos Biológicos , Sefarose , Óleos de Silicone , Análise de Célula Única/instrumentação , Análise de Célula Única/métodos , Viscosidade
12.
Proc Natl Acad Sci U S A ; 114(18): E3709-E3718, 2017 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-28420791

RESUMO

According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.


Assuntos
Apoptose , Sistema Nervoso Entérico/metabolismo , Nestina/metabolismo , Neurogênese , Receptores de Fator de Crescimento Neural/metabolismo , Fatores de Transcrição SOXE/metabolismo , Animais , Humanos , Camundongos , Camundongos Transgênicos , Nestina/genética , Receptores de Fator de Crescimento Neural/genética , Fatores de Transcrição SOXE/genética
14.
Sci Signal ; 10(469)2017 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-28270556

RESUMO

The factors that govern T cell activation control the initiation and progression of adaptive immune responses. T cells recognize their cognate antigen on the surface of antigen-presenting cells (APCs) through the T cell receptor, which results in the formation of a contact region (immune synapse) between the two cells and the activation of the T cells. Activated T cells proliferate and differentiate into effector T cells that secrete cytokines, provide help to B cells, and kill target cells. We asked whether the actin cytoskeleton governs differences in signaling in effector T cells versus naïve (unstimulated) T cells. Using atomic force microscopy and quantitative confocal microscopy, we found that naïve T cells had a mechanically stiffer cortical cytoskeleton than that of effector cells, which resulted in naïve cells forming smaller immune synapses with APCs. This suggests that the cytoskeletal stiffness of the T cell before it undergoes antigen stimulation predicts its subsequent dynamic engagement with APCs and its activation potential. Cytoskeletal rigidity depended on the activity of the actin-severing enzyme cofilin through a pathway requiring the small guanosine triphosphatase RhoA and the kinases ROCK (Rho-activated kinase) and LIMK. These findings suggest that the baseline cytoskeletal state controls T cell responses and that the underlying pathway could be a therapeutic target for modulating adaptive immunity.


Assuntos
Citoesqueleto de Actina/imunologia , Imunidade Adaptativa/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Citoesqueleto de Actina/metabolismo , Imunidade Adaptativa/genética , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Western Blotting , Linhagem Celular Tumoral , Quinases Lim/imunologia , Quinases Lim/metabolismo , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Força Atômica , Microscopia Confocal , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/genética , Quinases Associadas a rho/imunologia , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/imunologia , Proteína rhoA de Ligação ao GTP/metabolismo
15.
Biomaterials ; 115: 155-166, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889666

RESUMO

Native vascular extracellular matrices (vECM) consist of elastic fibers that impart varied topographical properties, yet most in vitro models designed to study the effects of topography on cell behavior are not representative of native architecture. Here, we engineer an electrospun elastin-like protein (ELP) system with independently tunable, vECM-mimetic topography and demonstrate that increasing topographical variation causes loss of endothelial cell-cell junction organization. This loss of VE-cadherin signaling and increased cytoskeletal contractility on more topographically varied ELP substrates in turn promote YAP activation and nuclear translocation, resulting in significantly increased endothelial cell migration and proliferation. Our findings identify YAP as a required signaling factor through which fibrous substrate topography influences cell behavior and highlights topography as a key design parameter for engineered biomaterials.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Células Endoteliais/citologia , Células Endoteliais/fisiologia , Matriz Extracelular/química , Mecanotransdução Celular/fisiologia , Animais , Materiais Biomiméticos/química , Células Cultivadas , Ratos , Ratos Endogâmicos F344 , Estresse Mecânico , Propriedades de Superfície , Tecidos Suporte
16.
Am J Respir Cell Mol Biol ; 56(1): 109-120, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27598620

RESUMO

The extracellular matrix in asthmatic lungs contains abundant low-molecular-weight hyaluronan, and this is known to promote antigen presentation and allergic responses. Conversely, high-molecular-weight hyaluronan (HMW-HA), typical of uninflamed tissues, is known to suppress inflammation. We investigated whether HMW-HA can be adapted to promote tolerance to airway allergens. HMW-HA was thiolated to prevent its catabolism and was tethered to allergens via thiol linkages. This platform, which we call "XHA," delivers antigenic payloads in the context of antiinflammatory costimulation. Allergen/XHA was administered intranasally to mice that had been sensitized previously to these allergens. XHA prevents allergic airway inflammation in mice sensitized previously to either ovalbumin or cockroach proteins. Allergen/XHA treatment reduced inflammatory cell counts, airway hyperresponsiveness, allergen-specific IgE, and T helper type 2 cell cytokine production in comparison with allergen alone. These effects were allergen specific and IL-10 dependent. They were durable for weeks after the last challenge, providing a substantial advantage over the current desensitization protocols. Mechanistically, XHA promoted CD44-dependent inhibition of nuclear factor-κB signaling, diminished dendritic cell maturation, and reduced the induction of allergen-specific CD4 T-helper responses. XHA and other potential strategies that target CD44 are promising alternatives for the treatment of asthma and allergic sinusitis.


Assuntos
Alérgenos/imunologia , Ácido Hialurônico/química , Ácido Hialurônico/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Células da Medula Óssea/citologia , Diferenciação Celular/efeitos dos fármacos , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Reagentes para Ligações Cruzadas/metabolismo , Células Dendríticas/efeitos dos fármacos , Receptores de Hialuronatos/metabolismo , Imunização , Interleucina-10 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Peso Molecular , NF-kappa B/metabolismo , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/fisiopatologia , Transporte Proteico/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo
17.
FASEB J ; 31(3): 868-881, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27903619

RESUMO

The cytokine IL-10 has potent antifibrotic effects in models of adult fibrosis, but the mechanisms of action are unclear. Here, we report a novel finding that IL-10 triggers a signal transducer and activator of transcription 3 (STAT3)-dependent signaling pathway that regulates hyaluronan (HA) metabolism and drives adult fibroblasts to synthesize an HA-rich pericellular matrix, which mimics the fetal regenerative wound healing phenotype with reduced fibrosis. By using cre-lox-mediated novel, inducible, fibroblast-, keratinocyte-, and wound-specific STAT3-knockdown postnatal mice-plus syngeneic fibroblast cell-transplant models-we demonstrate that the regenerative effects of IL-10 in postnatal wounds are dependent on HA synthesis and fibroblast-specific STAT3-dependent signaling. The importance of IL-10-induced HA synthesis for regenerative wound healing is demonstrated by inhibition of HA synthesis in a murine wound model by administering 4-methylumbelliferone. Although IL-10 and STAT3 signaling were intact, the antifibrotic repair phenotype that is induced by IL-10 overexpression was abrogated in this model. Our data show a novel role for IL-10 beyond its accepted immune-regulatory mechanism. The opportunity for IL-10 to regulate a fibroblast-specific formation of a regenerative, HA-rich wound extracellular matrix may lead to the development of innovative therapies to attenuate postnatal fibrosis in organ systems or diseases in which dysregulated inflammation and HA intersect.-Balaji, S., Wang, X., King, A., Le, L. D., Bhattacharya, S. S., Moles, C. M., Butte, M. J., de Jesus Perez, V. A., Liechty, K. W., Wight, T. N., Crombleholme, T. M., Bollyky, P. L., Keswani, S. G. Interleukin-10-mediated regenerative postnatal tissue repair is dependent on regulation of hyaluronan metabolism via fibroblast-specific STAT3 signaling.


Assuntos
Fibroblastos/metabolismo , Ácido Hialurônico/metabolismo , Interleucina-10/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Cicatrização , Animais , Células Cultivadas , Matriz Extracelular/metabolismo , Fibroblastos/fisiologia , Interleucina-10/genética , Queratinócitos/metabolismo , Queratinócitos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Fator de Transcrição STAT3/genética
20.
J Cell Biol ; 213(5): 535-42, 2016 06 06.
Artigo em Inglês | MEDLINE | ID: mdl-27241914

RESUMO

Triggering of the T cell receptor (TCR) integrates both binding kinetics and mechanical forces. To understand the contribution of the T cell cytoskeleton to these forces, we triggered T cells using a novel application of atomic force microscopy (AFM). We presented antigenic stimulation using the AFM cantilever while simultaneously imaging with optical microscopy and measuring forces on the cantilever. T cells respond forcefully to antigen after calcium flux. All forces and calcium responses were abrogated upon treatment with an F-actin inhibitor. When we emulated the forces of the T cell using the AFM cantilever, even these actin-inhibited T cells became activated. Purely mechanical stimulation was not sufficient; the exogenous forces had to couple through the TCR. These studies suggest a mechanical-chemical feedback loop in which TCR-triggered T cells generate forceful contacts with antigen-presenting cells to improve access to antigen.


Assuntos
Ativação Linfocitária , Linfócitos T/imunologia , Animais , Antígenos/metabolismo , Fenômenos Biomecânicos/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Cálcio/metabolismo , Linhagem Celular , Ativação Linfocitária/efeitos dos fármacos , Camundongos Transgênicos , Microscopia de Força Atômica , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos , Tiazolidinas/farmacologia
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