RESUMO
Inhibitors against the p110δ isoform of phosphoinositide-3-OH kinase (PI(3)K) have shown remarkable therapeutic efficacy in some human leukaemias. As p110δ is primarily expressed in leukocytes, drugs against p110δ have not been considered for the treatment of solid tumours. Here we report that p110δ inactivation in mice protects against a broad range of cancers, including non-haematological solid tumours. We demonstrate that p110δ inactivation in regulatory T cells unleashes CD8(+) cytotoxic T cells and induces tumour regression. Thus, p110δ inhibitors can break tumour-induced immune tolerance and should be considered for wider use in oncology.
Assuntos
Inibidores Enzimáticos/farmacologia , Tolerância Imunológica/efeitos dos fármacos , Neoplasias/enzimologia , Neoplasias/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Antineoplásicos/farmacologia , Ativação Enzimática/efeitos dos fármacos , Tolerância Imunológica/imunologia , Camundongos , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologiaRESUMO
PTEN, one of the most commonly mutated or lost tumor suppressors in human cancers, antagonizes signaling by the PI3K pathway. Mice with thymocyte-specific deletion of Pten rapidly develop peripheral lymphomas and autoimmunity, which may be caused by failed negative selection of thymocytes or from dysregulation of postthymic T cells. We induced conditional deletion of Pten from CD4 Th cells using a Cre knocked into the Tnfrsf4 (OX40) locus to generate OX40(Cre)Pten(f) mice. Pten-deficient Th cells proliferated more and produced greater concentrations of cytokines. The OX40(Cre)Pten(f) mice had a general increase in the number of lymphocytes in the lymph nodes, but not in the spleen. When transferred into wild-type (WT) mice, Pten-deficient Th cells enhanced anti-Listeria responses and the clearance of tumors under conditions in which WT T cells had no effect. Moreover, inflammatory responses were exaggerated and resolved later in OX40(Cre)Pten(f) mice than in WT mice. However, in contrast with models of thymocyte-specific Pten deletion, lymphomas and autoimmunity were not observed, even in older OX40(Cre)Pten(f) mice. Hence loss of Pten enhances Th cell function without obvious deleterious effects.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Homeostase/imunologia , PTEN Fosfo-Hidrolase/imunologia , Animais , Autoimunidade , Western Blotting , Citometria de Fluxo , Técnicas de Introdução de Genes , Ativação Linfocitária/imunologia , Linfoma/imunologia , Camundongos , Camundongos Transgênicos , Transdução de Sinais/imunologiaRESUMO
We have previously described critical and nonredundant roles for the phosphoinositide 3-kinase p110delta during the activation and differentiation of naive T cells, and p110delta inhibitors are currently being developed for clinical use. However, to effectively treat established inflammatory or autoimmune diseases, it is important to be able to inhibit previously activated or memory T cells. In this study, using the isoform-selective inhibitor IC87114, we show that sustained p110delta activity is required for interferon-gamma production. Moreover, acute inhibition of p110delta inhibits cytokine production and reduces hypersensitivity responses in mice. Whether p110delta played a similar role in human T cells was unknown. Here we show that IC87114 potently blocked T-cell receptor-induced phosphoinositide 3-kinase signaling by both naive and effector/memory human T cells. Importantly, IC87114 reduced cytokine production by memory T cells from healthy and allergic donors and from inflammatory arthritis patients. These studies establish that previously activated memory T cells are at least as sensitive to p110delta inhibition as naive T cells and show that mouse models accurately predict p110delta function in human T cells. There is therefore a strong rationale for p110delta inhibitors to be considered for therapeutic use in T-cell-mediated autoimmune and inflammatory diseases.
Assuntos
Linfócitos T CD4-Positivos/enzimologia , Linfócitos T CD4-Positivos/imunologia , Citocinas/biossíntese , Imunidade/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Artrite/enzimologia , Artrite/imunologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases , Humanos , Hipersensibilidade/enzimologia , Hipersensibilidade/imunologia , Imunidade/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Memória Imunológica/imunologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Inibidores de Fosfoinositídeo-3 Quinase , Quinazolinas/farmacologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
The generation of high-affinity Abs is essential for immunity and requires collaboration between B and T cells within germinal centers (GCs). By using novel mouse models with a conditional deletion of the p110δ catalytic subunit of the PI3K pathway, we established that p110δ is required in T cells, but not in B cells, for the GC reaction. We found the formation of T follicular helper (T(FH)) cells to be critically dependent on p110δ in T cells. Furthermore, by deleting phosphatase and tensin homolog deleted on chromosome 10, which opposes p110δ in activated T cells, we found a positive correlation between increased numbers of T(FH) cells and GC B cells. These results are consistent with the hypothesis that T cell help is the limiting factor in the GC reaction. P110δ was not required for the expression of B cell lymphoma 6, the downregulation of CCR7, or T cell entry into primary follicles. Instead, p110δ was the critical catalytic subunit for ICOS downstream signaling and the production of key T(FH) cytokines and effector molecules. Our findings support a model in which the magnitude of the GC reaction is controlled by the activity of the PI3K pathway in T(FH) cells.
Assuntos
Formação de Anticorpos/imunologia , Centro Germinativo/imunologia , Ativação Linfocitária/imunologia , Fosfatidilinositol 3-Quinases/metabolismo , Linfócitos T Auxiliares-Indutores/enzimologia , Transferência Adotiva , Animais , Linfócitos B/imunologia , Western Blotting , Separação Celular , Classe I de Fosfatidilinositol 3-Quinases , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Centro Germinativo/enzimologia , Camundongos , Camundongos Transgênicos , Microscopia de Fluorescência , Fosfatidilinositol 3-Quinases/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologiaRESUMO
Regulatory T cells (Tregs) prevent autoimmunity and inflammation by suppressing the activation of other T cells and antigen presenting cells. The role of phosphoinositide 3-kinase (PI3K) signaling in Treg is controversial. Some studies suggest that inhibition of the PI3K pathway is essential for the development of Tregs whereas other studies have shown reduced Treg numbers and function when PI3K activity is suppressed. Here we attempt to reconcile the different studies that have explored PI3K and the downstream effectors Akt, Foxo, and mTOR in regulatory T cell development and function and discuss the implications for health and therapeutic intervention.
RESUMO
The PI3K pathway has emerged as a key regulator of regulatory T cell (Treg) development and homeostasis and is required for full Treg-mediated suppression. To identify new genes involved in PI3K-dependent suppression, we compared the transcriptome of WT and p110δ(D910A) Tregs. Among the genes that were differentially expressed was the gene for the transmembrane cyclic ADP ribose hydrolase CD38. Here we show that CD38 is expressed mainly by a subset of Foxp3(+)CD25(+)CD4(+) T cells originating in the thymus and on Tregs in the spleen. CD38(high) WT Tregs showed superior suppressive activity to CD38(low) Tregs, which failed to upregulate CD73, a surface protein which is important for suppression. However, Tregs from heterozygous CD38(+/-) mice were unimpaired despite lower levels of CD38 expression. Therefore, CD38 can be used as a marker for Tregs with high suppressive activity and the impaired Treg function in p110δ(D910A) mice can in part be explained by the failure of CD38(high) cells to develop.
Assuntos
ADP-Ribosil Ciclase 1/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Linfócitos T Reguladores/enzimologia , ADP-Ribosil Ciclase 1/genética , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases , Fatores de Transcrição Forkhead/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Genoma/genética , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/metabolismo , Camundongos , Quinazolinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Tretinoína/farmacologiaRESUMO
MicroRNAs are a class of small RNAs that are increasingly being recognized as important regulators of gene expression. Although hundreds of microRNAs are present in the mammalian genome, genetic studies addressing their physiological roles are at an early stage. We have shown that mice deficient for bic/microRNA-155 are immunodeficient and display increased lung airway remodeling. We demonstrate a requirement of bic/microRNA-155 for the function of B and T lymphocytes and dendritic cells. Transcriptome analysis of bic/microRNA-155-deficient CD4+ T cells identified a wide spectrum of microRNA-155-regulated genes, including cytokines, chemokines, and transcription factors. Our work suggests that bic/microRNA-155 plays a key role in the homeostasis and function of the immune system.