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1.
Front Oncol ; 12: 884196, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35664753

RESUMO

Therapeutic blockade of the CD47/SIRPα axis by small molecules or monoclonal antibodies (mAbs) is a proven strategy to enhance macrophages-mediated anti-tumor activity. However, this strategy has been hampered by elevated on-target toxicities and rapid clearance due to the extensive CD47 expression on normal cells ("antigen sink") such as red blood cells (RBCs). To address these hurdles, we report on the development of STI-6643, an affinity-engineered fully human anti-CD47 IgG4 antibody with negligible binding to normal cells. STI-6643 exhibited no hemagglutination activity on human RBCs at concentrations up to 300 µg/mL yet specifically blocked the CD47/SIPRα interaction. Of particular interest, STI-6643 preserved T cell functionality in vitro and showed significantly lower immune cell depletion in vivo in contrast to three previously published competitor reference anti-CD47 clones Hu5F9, AO-176 and 13H3. In cynomolgus monkeys, STI-6643 was well-tolerated at the highest dose tested (300 mg/kg/week) and provided favorable clinical safety margins. Finally, STI-6643 displayed comparable anti-tumor activity to the high-affinity reference clone Hu5F9 in a RAJI-Fluc xenograft tumor model as monotherapy or in combination with anti-CD20 (rituximab) or anti-CD38 (daratumumab) mAbs. These data suggest that STI-6643 possesses the characteristics of an effective therapeutic candidate given its potent anti-tumor activity and low toxicity profile.

2.
J Immunother Cancer ; 9(9)2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34588224

RESUMO

BACKGROUND: Our previous studies revealed a critical role of a novel CTLA4-protein kinase C-eta (PKCη) signaling axis in mediating the suppressive activity of regulatory T cells (Tregs) in antitumor immunity. These studies have employed adoptive transfer of germline PKCη-deficient (Prkch-/-) Tregs into Prkch+/+ mice prior to tumor implantation. Here, we extended these findings into a biologically and clinically more relevant context. METHODS: We have analyzed the role of PKCη in antitumor immunity and the tumor microenvironment (TME) in intact tumor-bearing mice with Treg-specific or CD8+ T cell-specific Prkch deletion, including in a therapeutic model of combinatorial treatment. In addition to measuring tumor growth, we analyzed the phenotype and functional attributes of tumor-infiltrating immune cells, particularly Tregs and dendritic cells (DCs). RESULTS: Using two models of mouse transplantable cancer and a genetically engineered autochthonous hepatocellular carcinoma (HCC) model, we found, first, that mice with Treg-specific Prkch deletion displayed a significantly reduced growth of B16-F10 melanoma and TRAMP-C1 adenocarcinoma tumors. Tumor growth reduction was associated with a less immunosuppressive TME, indicated by increased numbers and function of tumor-infiltrating CD8+ effector T cells and elevated expression of the costimulatory ligand CD86 on intratumoral DCs. In contrast, CD8+ T cell-specific Prkch deletion had no effect on tumor growth or the abundance and functionality of CD8+ effector T cells, consistent with findings that Prkch-/- CD8+ T cells proliferated normally in response to in vitro polyclonal or specific antigen stimulation. Similar beneficial antitumor effects were found in mice with germline or Treg-specific Prkch deletion that were induced to develop an autochthonous HCC. Lastly, using a therapeutic model, we found that monotherapies consisting of Treg-specific Prkch deletion or vaccination with irradiated Fms-like tyrosine kinase 3 ligand (Flt3L)-expressing B16-F10 tumor cells post-tumor implantation significantly delayed tumor growth. This effect was more pronounced in mice receiving a combination of the two immunotherapies. CONCLUSION: These findings demonstrate the potential utility of PKCη inhibition as a viable clinical approach to treat patients with cancer, especially when combined with adjuvant therapies.


Assuntos
Antígeno CTLA-4/metabolismo , Imunoterapia/métodos , Neoplasias/tratamento farmacológico , Animais , Humanos , Camundongos , Neoplasias/genética , Linfócitos T Reguladores
3.
J Immunol ; 204(9): 2439-2446, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32198145

RESUMO

We reported that protein kinase C-η (PKCη) forms a novel (to our knowledge) signaling complex with the checkpoint inhibitory protein CTLA-4 in regulatory T cells (Tregs). This complex is required for the contact-dependent suppressive activity of Tregs, including suppression of antitumor immunity. However, the importance of PKCη in protective immunity mediated by T effector cells remains unclear. We used mice with germline or conditional Treg-specific deletion of Prkch, the PKCη-encoding gene, to explore CD8+ T cell-dependent antiviral immunity using the lymphocytic choriomeningitis virus Armstrong strain acute infection model as well as the in vitro activation of murine or human CD8+ T cells. Five days following infection, germline Prkch -/- mice displayed enhanced viral clearance compared with control mice. Similarly, Prkch Treg-specific conditional knockout mice also showed improved viral clearance and displayed enhanced expression of granzyme B and IFN-γ by both virus-specific and total CD8+ T cells, demonstrating that enhanced viral clearance in germline Prkch -/- mice is caused by PKCη deficiency in Tregs and the resulting functional defect of Prkch -/- Tregs. In addition, purified Prkch -/- mouse CD8+ T cells as well as PRKCH knockdown human CD8+ T cells displayed intact, or even enhanced, T cell activation in vitro as measured by proliferation and expression of granzyme B and IFN-γ. Thus, global PKCη deletion does not impair overall CD8+ T cell-mediated immunity, including antiviral immunity, implying that selective pharmacological PKCη inhibition could be safely used in vivo to inhibit undesired contact-dependent suppression by Tregs and, thus, enhance tumor-specific and, likely, virus-specific immunity.


Assuntos
Linfócitos T CD8-Positivos , Ativação Linfocitária , Proteína Quinase C , Linfócitos T Reguladores , Viroses , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Antígeno CTLA-4/imunologia , Granzimas/imunologia , Células HEK293 , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Interferon gama/imunologia , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos Knockout , Proteína Quinase C/deficiência , Proteína Quinase C/imunologia , Inibidores de Proteínas Quinases/imunologia , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Viroses/imunologia
4.
Front Immunol ; 9: 2412, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405612

RESUMO

Follicular helper T (TFH) cells represent a highly specialized CD4+ T cell subpopulation that supports the generation of germinal centers (GC) and provides B cells with critical signals promoting antibody class switching, generation of high affinity antibodies, and memory formation. TFH cells are characterized by the expression of the chemokine receptor CXCR5, the transcription factor Bcl-6, costimulatory molecules ICOS, and PD-1, and the production of cytokine IL-21. The acquisition of a TFH phenotype is a complex and multistep process that involves signals received through engagement of the TCR along with a multitude of costimulatory molecules and cytokines receptors. Members of the Tumor necrosis factor Receptor Associated Factors (TRAF) represent one of the major classes of signaling mediators involved in the differentiation and functions of TFH cells. TRAF molecules are the canonical adaptor molecules that physically interact with members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) and actively modulate their downstream signaling cascades through their adaptor function and/or E3 ubiquitin ligase activity. OX-40, GITR, and 4-1BB are the TRAF-dependent TNFRSF members that have been implicated in the differentiation and functions of TFH cells. On the other hand, emerging data demonstrate that TRAF proteins also participate in signaling from the TCR and CD28, which deliver critical signals leading to the differentiation of TFH cells. More intriguingly, we recently showed that the cytoplasmic tail of ICOS contains a conserved TANK-binding kinase 1 (TBK1)-binding motif that is shared with TBK1-binding TRAF proteins. The presence of this TRAF-mimicking signaling module downstream of ICOS is required to mediate the maturation step during TFH differentiation. In addition, JAK-STAT pathways emanating from IL-2, IL-6, IL-21, and IL-27 cytokine receptors affect TFH development, and crosstalk between TRAF-mediated pathways and the JAK-STAT pathways can contribute to generate integrated signals required to drive and sustain TFH differentiation. In this review, we will introduce the molecular interactions and the major signaling pathways controlling the differentiation of TFH cells. In each case, we will highlight the contributions of TRAF proteins to these signaling pathways. Finally, we will discuss the role of individual TRAF proteins in the regulation of T cell-dependent humoral responses.


Assuntos
Formação de Anticorpos/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/imunologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose Tumoral/metabolismo , Animais , Comunicação Celular/imunologia , Citocinas/metabolismo , Humanos , Ativação Linfocitária , NF-kappa B/metabolismo , Linfócitos T Auxiliares-Indutores/citologia
5.
JCI Insight ; 2(23)2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29212947

RESUMO

The ability of Tregs to control the development of immune responses is essential for maintaining immune system homeostasis. However, Tregs also inhibit the development of efficient antitumor responses. Here, we explored the characteristics and mechanistic basis of the Treg-intrinsic CTLA4/PKCη signaling pathway that we recently found to be required for contact-dependent Treg-mediated suppression. We show that PKCη is required for the Treg-mediated suppression of tumor immunity in vivo. The presence of PKCη-deficient (Prkch-/-) Tregs in the tumor microenvironment was associated with a significantly increased expression of the costimulatory molecule CD86 on intratumoral CD103+ DCs, enhanced priming of antigen-specific CD8+ T cells, and greater levels of effector cytokines produced by these cells. Similar to mouse Tregs, the GIT/PAK/PIX complex also operated downstream of CTLA4 and PKCη in human Tregs, and GIT2 knockdown in Tregs promoted antitumor immunity. Collectively, our data suggest that targeting the CTLA4/PKCη/GIT/PAK/PIX signaling pathway in Tregs could represent a novel immunotherapeutic strategy to alleviate the negative impact of Tregs on antitumor immune responses.


Assuntos
Antígeno CTLA-4/imunologia , Proteína Quinase C/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Antígeno B7-2/metabolismo , Feminino , Xenoenxertos , Humanos , Tolerância Imunológica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Melanoma Experimental/imunologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transplante de Neoplasias , Neoplasias da Próstata/imunologia , Transdução de Sinais/imunologia
7.
Nat Immunol ; 17(7): 825-33, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27135603

RESUMO

Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (TFH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) TFH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of TFH cells. These results reveal a previously unknown ICOS-TBK1 signaling pathway that specifies the commitment of GC TFH cells.


Assuntos
Linfócitos B/fisiologia , Linfócitos T CD4-Positivos/fisiologia , Centro Germinativo/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Formação de Anticorpos/genética , Diferenciação Celular/genética , Células Cultivadas , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Ligação Proteica , Proteínas Serina-Treonina Quinases/genética , Transdução de Sinais , Fator 2 Associado a Receptor de TNF/genética , Fator 3 Associado a Receptor de TNF/genética
8.
World J Gastroenterol ; 22(3): 974-95, 2016 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-26811641

RESUMO

In the gut, where billions of non-self-antigens from the food and the microbiota are present, the immune response must be tightly regulated to ensure both host protection against pathogenic microorganisms and the absence of immune-related pathologies. It has been well documented that regulatory T cells (Tregs) play a pivotal role in this context. Indeed, Tregs are able to prevent excessive inflammation, which can lead to the rupture of intestinal homeostasis observed in inflammatory bowel diseases (IBDs). Both the worldwide incidence and prevalence of such diseases have increased throughout the latter part of the 20(th) century. Therefore, it is crucial to understand how Tregs suppress the colitogenic immune cells to establish new treatments for patients suffering from IBDs. In this review, we will first summarize the results obtained in animal model studies that highlight the importance of Tregs in maintaining intestinal homeostasis and describe the specific suppressive mechanisms involved. Next, our current knowledge about Tregs contribution to human IBDs will be reviewed, as well as the current therapeutic perspective on using Tregs for clinical IBD treatment and the challenges that remain to be resolved to ensure both the safety and effectiveness of these therapies in targeting this critical immune-regulatory cell population.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Intestinos/imunologia , Linfócitos T Reguladores/imunologia , Animais , Fármacos Gastrointestinais/uso terapêutico , Microbioma Gastrointestinal , Homeostase , Interações Hospedeiro-Patógeno , Humanos , Imunossupressores/uso terapêutico , Imunoterapia/métodos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Doenças Inflamatórias Intestinais/metabolismo , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/terapia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Fenótipo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia
9.
J Immunol ; 195(4): 1608-16, 2015 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-26163585

RESUMO

The development of inflammatory diseases depends on complex interactions between several genes and various environmental factors. Discovering new genetic risk factors and understanding the mechanisms whereby they influence disease development is of paramount importance. We previously reported that deficiency in Themis1, a new actor of TCR signaling, impairs regulatory T cell (Treg) function and predisposes Brown-Norway (BN) rats to spontaneous inflammatory bowel disease (IBD). In this study, we reveal that the epistasis between Themis1 and Vav1 controls the occurrence of these phenotypes. Indeed, by contrast with BN rats, Themis1 deficiency in Lewis rats neither impairs Treg suppressive functions nor induces pathological manifestations. By using congenic lines on the BN genomic background, we show that the impact of Themis1 deficiency on Treg suppressive functions depends on a 117-kb interval coding for a R63W polymorphism that impacts Vav1 expression and functions. Indeed, the introduction of a 117-kb interval containing the Lewis Vav1-R63 variant restores Treg function and protects Themis1-deficient BN rats from spontaneous IBD development. We further show that Themis1 binds more efficiently to the BN Vav1-W63 variant and is required to stabilize its recruitment to the transmembrane adaptor LAT and to fully promote the activation of Erk kinases. Together, these results highlight the importance of the signaling pathway involving epistasis between Themis1 and Vav1 in the control of Treg suppressive function and susceptibility to IBD development.


Assuntos
Epistasia Genética , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Proto-Oncogênicas c-vav/genética , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Citocinas/biossíntese , Modelos Animais de Doenças , Feminino , Doenças Inflamatórias Intestinais/patologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Mutação , Proteínas Proto-Oncogênicas c-vav/metabolismo , Ratos , Ratos Transgênicos , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
10.
J Exp Med ; 211(9): 1779-92, 2014 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-25073791

RESUMO

Interventional strategies to treat atherosclerosis, such as transluminal angioplasty and stent implantation, often cause vascular injury. This leads to intimal hyperplasia (IH) formation that induces inflammatory and fibroproliferative processes and ultimately restenosis. We show that phosphoinositide 3-kinase γ (PI3Kγ) is a key player in IH formation and is a valid therapeutic target in its prevention/treatment. PI3Kγ-deficient mice and mice expressing catalytically inactive PI3Kγ (PI3Kγ KD) showed reduced arterial occlusion and accumulation of monocytes and T cells around sites of vascular lesion. The transfer of PI3Kγ KD CD4(+) T cells into Rag2-deficient mice greatly reduced vascular occlusion compared with WT cells, clearly demonstrating the involvement of PI3Kγ in CD4(+) T cells during IH formation. In addition we found that IH is associated with increased levels of Th1 and Th17 cytokines. A specific decrease in the Th1 response was observed in the absence of PI3Kγ activity, leading to decreased CXCL10 and RANTES production by smooth muscle cells. Finally, we show that treatment with the PI3Kγ inhibitor AS-605240 is sufficient to decrease IH in both mouse and rat models, reinforcing the therapeutic potential of PI3Kγ inhibition. Altogether, these findings demonstrate a new role for PI3Kγ activity in Th1-controlled IH development.


Assuntos
Neointima/enzimologia , Neointima/imunologia , Inibidores de Fosfoinositídeo-3 Quinase , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Animais , Lesões das Artérias Carótidas/tratamento farmacológico , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/imunologia , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Inibidores Enzimáticos/farmacologia , Artéria Femoral/enzimologia , Artéria Femoral/imunologia , Artéria Femoral/lesões , Marcação de Genes , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neointima/tratamento farmacológico , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tiazolidinedionas/farmacologia
11.
PLoS Genet ; 8(1): e1002461, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22275874

RESUMO

Spontaneous or chemically induced germline mutations, which lead to Mendelian phenotypes, are powerful tools to discover new genes and their functions. Here, we report an autosomal recessive mutation that occurred spontaneously in a Brown-Norway (BN) rat colony and was identified as causing marked T cell lymphopenia. This mutation was stabilized in a new rat strain, named BN(m) for "BN mutated." In BN(m) rats, we found that the T cell lymphopenia originated in the thymus, was intrinsic to CD4 T lymphocytes, and was associated with the development of an inflammatory bowel disease. Furthermore, we demonstrate that the suppressive activity of both peripheral and thymic CD4(+) CD25(bright) regulatory T cells (Treg) is defective in BN(m) rats. Complementation of mutant animals with BN Treg decreases disease incidence and severity, thus suggesting that the impaired Treg function is involved in the development of inflammatory bowel disease in BN(m) rats. Moreover, the cytokine profile of effector CD4 T cells is skewed toward Th2 and Th17 phenotypes in BN(m) rats. Linkage analysis and genetic dissection of the CD4 T cell lymphopenia in rats issued from BN(m)×DA crosses allowed the localization of the mutation on chromosome 1, within a 1.5 megabase interval. Gene expression and sequencing studies identified a frameshift mutation caused by a four-nucleotide insertion in the Themis gene, leading to its disruption. This result is the first to link Themis to the suppressive function of Treg and to suggest that, in Themis-deficient animals, defect of this function is involved in intestinal inflammation. Thus, this study highlights the importance of Themis as a new target gene that could participate in the pathogenesis of immune diseases characterized by chronic inflammation resulting from a defect in the Treg compartment.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Mutação da Fase de Leitura , Doenças Inflamatórias Intestinais/genética , Linfopenia/genética , Linfócitos T Reguladores/metabolismo , Timo/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Mapeamento Cromossômico , Ligação Genética , Doenças Inflamatórias Intestinais/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ratos , Células Th17/metabolismo , Células Th2/metabolismo
12.
Int Immunol ; 23(10): 625-36, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21930595

RESUMO

The rat is an important biomedical experimental model that benefited from the recent development of new transgenic and knockout techniques. With the goal to optimize rat mAb production and to analyze the impact of Bcl-2 on B-cell development, we generated bcl-2 transgenic rats. Transgenic rats showed Bcl-2 over-expression in B cells, increased B cell numbers in lymphoid organs, elevated production of immunoglobulins (Igs) and prolonged B-cell survival in vitro. Transgenic rats remained healthy, reproduced normally and did not develop autoimmunity. Fusions with bcl-2 transgenic splenocytes did not result in increased hybridoma generation. A comparison of on- and off-rates of 39 mAbs generated with bcl-2 transgenic and wild-type animals revealed no significant differences. Over-expression of Bcl-2 in hybridomas did not change cell proliferation but resulted in increased Ig production. Bcl-2 transgenic rats will be a useful tool for the generation of rat mAbs, the analysis of B cells in different pathophysiological models, such as autoimmunity, cancer or organ transplantation, and the study of rat B-cell biology.


Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Hibridomas/imunologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Linfócitos B/citologia , Imunoglobulinas/biossíntese , Imunoglobulinas/imunologia , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
13.
J Exp Med ; 208(11): 2183-91, 2011 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-21948080

RESUMO

CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural T(reg) cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of T(reg) cells in the thymus and peripheral lymphoid organs, without impacting the size of the T(conv) cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca(2+) flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural T(reg) cell development.


Assuntos
Fatores de Transcrição Forkhead/metabolismo , Polimorfismo Genético , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo , Linfócitos T Reguladores/fisiologia , Animais , Animais Congênicos , Arginina/genética , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/fisiologia , Células Cultivadas , Cromossomos de Mamíferos/genética , Fatores de Transcrição Forkhead/genética , Células HEK293 , Humanos , Ratos , Ratos Endogâmicos Lew , Linfócitos T Reguladores/citologia , Quimeras de Transplante , Triptofano/genética
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