RESUMO
Chimeric antigen receptor (CAR) T cells have been used to successfully treat various blood cancers, but adverse effects have limited their potential. Here, we developed chimeric adaptor proteins (CAPs) and CAR tyrosine kinases (CAR-TKs) in which the intracellular ζ T cell receptor (TCRζ) chain was replaced with intracellular protein domains to stimulate signaling downstream of the TCRζ chain. CAPs contain adaptor domains and the kinase domain of ZAP70, whereas CAR-TKs contain only ZAP70 domains. We hypothesized that CAPs and CAR-TKs would be more potent than CARs because they would bypass both the steps that define the signaling threshold of TCRζ and the inhibitory regulation of upstream molecules. CAPs were too potent and exhibited high tonic signaling in vitro. In contrast, CAR-TKs exhibited high antitumor efficacy and significantly enhanced long-term tumor clearance in leukemia-bearing NSG mice as compared with the conventional CD19-28ζ-CAR-T cells. CAR-TKs were activated in a manner independent of the kinase Lck and displayed slower phosphorylation kinetics and prolonged signaling compared with the 28ζ-CAR. Lck inhibition attenuated CAR-TK cell exhaustion and improved long-term function. The distinct signaling properties of CAR-TKs may therefore be harnessed to improve the in vivo efficacy of T cells engineered to express an antitumor chimeric receptor.
Assuntos
Receptores de Antígenos de Linfócitos T , Receptores de Antígenos Quiméricos , Transdução de Sinais , Linfócitos T , Animais , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/genética , Humanos , Transdução de Sinais/imunologia , Camundongos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Proteína-Tirosina Quinase ZAP-70/metabolismo , Proteína-Tirosina Quinase ZAP-70/genética , Proteína-Tirosina Quinase ZAP-70/imunologia , Imunoterapia Adotiva/métodos , Camundongos Endogâmicos NOD , Linhagem Celular Tumoral , FosforilaçãoRESUMO
Group 2 innate lymphoid cells (ILC2s) expressing IL-5 and IL-13 are localized at various mucosal tissues and play critical roles in the induction of type 2 inflammation, response to helminth infection, and tissue repair. Here, we reveal a unique ILC2 subset in the mouse intestine that constitutively expresses IL-4 together with GATA3, ST2, KLRG1, IL-17RB, and IL-5. In this subset, IL-4 expression is regulated by mechanisms similar to but distinct from those observed in T cells and is partly affected by IL-25 signaling. Although the absence of the microbiota had marginal effects, feeding mice with a vitamin B1-deficient diet compromised the number of intestinal IL-4+ ILC2s. The decrease in the number of IL-4+ ILC2s caused by the vitamin B1 deficiency was accompanied by a reduction in IL-25-producing tuft cells. Our findings reveal that dietary vitamin B1 plays a critical role in maintaining interaction between tuft cells and IL-4+ ILC2s, a previously uncharacterized immune cell population that may contribute to maintaining intestinal homeostasis.
Assuntos
Dieta , Mucosa Intestinal , Tiamina , Animais , Camundongos , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Tiamina/metabolismo , Organismos Livres de Patógenos Específicos , Camundongos Endogâmicos C57BL , Interleucina-4/metabolismo , Microbioma Gastrointestinal , Organoides/citologia , Organoides/imunologia , Ácido TrinitrobenzenossulfônicoRESUMO
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an ultra-rare combined primary immunodeficiency disease caused by heterozygous gain-of-function mutations in the chemokine receptor CXCR4. WHIM patients typically present with recurrent acute infections associated with myelokathexis (severe neutropenia due to bone marrow retention of mature neutrophils). Severe lymphopenia is also common, but the only associated chronic opportunistic pathogen is human papillomavirus and mechanisms are not clearly defined. In this study, we show that WHIM mutations cause more severe CD8 than CD4 lymphopenia in WHIM patients and WHIM model mice. Mechanistic studies in mice revealed selective and WHIM allele dose-dependent accumulation of mature CD8 single-positive cells in thymus in a cell-intrinsic manner due to prolonged intrathymic residence, associated with increased CD8 single-positive thymocyte chemotactic responses in vitro toward the CXCR4 ligand CXCL12. In addition, mature WHIM CD8+ T cells preferentially home to and are retained in the bone marrow in mice in a cell-intrinsic manner. Administration of the specific CXCR4 antagonist AMD3100 (plerixafor) in mice rapidly and transiently corrected T cell lymphopenia and the CD4/CD8 ratio. After lymphocytic choriomeningitis virus infection, we found no difference in memory CD8+ T cell differentiation or viral load between wild-type and WHIM model mice. Thus, lymphopenia in WHIM syndrome may involve severe CXCR4-dependent CD8+ T cell deficiency resulting in part from sequestration in the primary lymphoid organs, thymus, and bone marrow.
Assuntos
Agamaglobulinemia , Compostos Heterocíclicos , Síndromes de Imunodeficiência , Linfopenia , Neutropenia , Humanos , Animais , Camundongos , Síndromes de Imunodeficiência/genética , Mobilização de Células-Tronco Hematopoéticas/efeitos adversos , Agamaglobulinemia/complicações , Agamaglobulinemia/genética , Neutropenia/genética , Linfócitos T CD8-Positivos , Receptores CXCR4/genéticaRESUMO
Personalized cancer vaccines are a promising approach for inducing T cell immunity to tumor neoantigens. Using a self-assembling nanoparticle vaccine that links neoantigen peptides to a Toll-like receptor 7/8 agonist (SNP-7/8a), we show how the route and dose alter the magnitude and quality of neoantigen-specific CD8+ T cells. Intravenous vaccination (SNP-IV) induced a higher proportion of TCF1+PD-1+CD8+ T cells as compared to subcutaneous immunization (SNP-SC). Single-cell RNA sequencing showed that SNP-IV induced stem-like genes (Tcf7, Slamf6, Xcl1) whereas SNP-SC enriched for effector genes (Gzmb, Klrg1, Cx3cr1). Stem-like cells generated by SNP-IV proliferated and differentiated into effector cells upon checkpoint blockade, leading to superior antitumor response as compared to SNP-SC in a therapeutic model. The duration of antigen presentation by dendritic cells controlled the magnitude and quality of CD8+ T cells. These data demonstrate how to optimize antitumor immunity by modulating vaccine parameters for specific generation of effector or stem-like CD8+ T cells.
Assuntos
Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Fator 1-alfa Nuclear de Hepatócito/análise , Nanopartículas , Animais , Apresentação de Antígeno , Vacinas Anticâncer/imunologia , Células Dendríticas/imunologia , Feminino , Imunidade Inata , Camundongos , Camundongos Endogâmicos C57BL , VacinaçãoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
CD4+ T lymphocytes consist of naïve, antigen-specific memory, and memory-phenotype (MP) cell compartments at homeostasis. We recently showed that MP cells exert innate-like effector function during host defense, but whether MP CD4+ T cells are functionally heterogeneous and, if so, what signals specify the differentiation of MP cell subpopulations under homeostatic conditions is still unclear. Here we characterize MP lymphocytes as consisting of T-bethigh, T-betlow, and T-bet- subsets, with innate, Th1-like effector activity exclusively associated with T-bethigh cells. We further show that the latter population depends on IL-12 produced by CD8α+ type 1 dendritic cells (DC1) for its differentiation. Finally, our data demonstrate that this tonic IL-12 production requires TLR-MyD88 signaling independent of foreign agonists, and is further enhanced by CD40-CD40L interactions between DC1 and CD4+ T lymphocytes. We propose that optimal differentiation of T-bethigh MP lymphocytes at homeostasis is driven by self-recognition signals at both the DC and Tcell levels.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Homeostase/imunologia , Memória Imunológica/imunologia , Proteínas com Domínio T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/imunologia , Antígenos CD40/metabolismo , Ligante de CD40/genética , Ligante de CD40/imunologia , Ligante de CD40/metabolismo , Antígenos CD8/imunologia , Antígenos CD8/metabolismo , Comunicação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-12/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Transdução de Sinais/imunologia , Proteínas com Domínio T/metabolismo , Células Th1/citologia , Células Th1/imunologia , Células Th1/metabolismoRESUMO
Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.
Assuntos
Adjuvantes Imunológicos/química , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Camundongos , Nanopartículas , Medicina de Precisão , Primatas , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Vacinação , Vacinas ConjugadasRESUMO
T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL-4+ Th2 cells in lymph node, but production of effector cytokines including IL-5 and IL-13 is thought to require additional signals from antigen and the environment. Here we report that a substantial proportion of naive CD4+ T cells in spleen and lymph node express receptors for the epithelium-derived inflammatory cytokine thymic stromal lymphopoietin (TSLP). Culture of naive CD4+ T cells in anti-(a)CD3, aCD28, and TSLP-supplemented Th2 conditions enabled the development of a unique population of IL-13-single positive (IL-13-SP) CD4+ T cells; TSLP and Th2 conditions were both required for their development. Sorting experiments revealed that IL-13-SP Th2 cells originated from IL-4-negative precursors and coexpressed transcripts for the Th2 cytokines IL-5 and IL-9. In vivo, high TSLP levels acted directly on CD4+ T cells to induce the development of IL-13-SP and IL-4+IL-13+ double-positive populations in lymph node. These cells were phenotypically similar to Th2 effector cells and were CXCR5lowPD1low and expressed low levels of Bcl6 and Il21 transcripts and high levels of Gata3, Il3, and Il5 Our findings suggest a role of TSLP in directly promoting Th2 cell effector function and support the notion of TSLP as a key driver of Th2 inflammation.
Assuntos
Citocinas/imunologia , Células Th2/imunologia , Transferência Adotiva , Animais , Diferenciação Celular/imunologia , Citocinas/deficiência , Citocinas/genética , Feminino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Receptores de Interleucina-7/metabolismo , Células Th2/classificação , Células Th2/citologia , Linfopoietina do Estroma do TimoRESUMO
Conventional CD4+ T cells are composed of naïve, pathogen-specific memory, and pathogen-independent memory-phenotype (MP) cells under steady state. Naïve and pathogen-specific memory cells play key roles in adaptive immunity, whereas the homeostatic mechanisms regulating the generation of MP cells and their biological functions are unclear. We show that MP cells are autonomously generated from peripheral naïve cells in the absence of infectious stimulation in a T cell receptor (TCR)- and CD28-dependent manner. We further demonstrate that MP cells contain a T-bethi subpopulation that is continuously generated by environmental interleukin-12 (IL-12) and rapidly produces interferon-γ (IFN-γ) in response to IL-12 in the absence of pathogen recognition. These cells can provide nonspecific host resistance against Toxoplasma gondii infection while enhancing the adaptive CD4+ T cell responses. Together, these findings reveal that MP cells are continuously generated from naïve precursors and have a previously undescribed innate immune function by which they produce an early, T helper cell type 1 (TH1)-like protective response against pathogens.
RESUMO
Activated retina-specific T cells that have acquired the ability to break through the blood-retinal barrier are thought to be causally involved in autoimmune uveitis, a major cause of human blindness. It is unclear where these autoreactive T cells first become activated, given that their cognate antigens are sequestered within the immune-privileged eye. We demonstrate in a novel mouse model of spontaneous uveitis that activation of retina-specific T cells is dependent on gut commensal microbiota. Retina-specific T cell activation involved signaling through the autoreactive T cell receptor (TCR) in response to non-cognate antigen in the intestine and was independent of the endogenous retinal autoantigen. Our findings not only have implications for the etiology of human uveitis, but also raise the possibility that activation of autoreactive TCRs by commensal microbes might be a more common trigger of autoimmune diseases than is currently appreciated.
Assuntos
Intestinos/imunologia , Microbiota/imunologia , Retina/imunologia , Linfócitos T/imunologia , Uveíte/imunologia , Animais , Antígenos de Bactérias/administração & dosagem , Autoantígenos/imunologia , Autoimunidade , Barreira Hematorretiniana/imunologia , Células Cultivadas , Modelos Animais de Doenças , Proteínas do Olho/genética , Proteínas do Olho/imunologia , Proteínas do Olho/metabolismo , Tolerância Imunológica , Intestinos/microbiologia , Ativação Linfocitária , Camundongos Endogâmicos , Camundongos Knockout , Receptores de Antígenos de Linfócitos T/metabolismo , Proteínas de Ligação ao Retinol/genética , Proteínas de Ligação ao Retinol/imunologia , Proteínas de Ligação ao Retinol/metabolismo , Uveíte/microbiologiaRESUMO
The cytokine thymic stromal lymphopoietin (TSLP) is produced by epithelia exposed to the contact sensitizer dibutyl phthalate (DBP), and it is critical for the induction of Th2 immune responses by DBP-FITC. TSLP is thought to act on dendritic cells (DC), but the precise DC subsets involved in the response to TSLP remain to be fully characterized. In this study we show that a subset of CD326(lo)CD103(lo)CD11b(lo) dermal DC, which we termed "triple-negative (TN) DC," is highly responsive to TSLP. In DBP-FITC-treated mice, TN DC upregulated expression of CD86 and rapidly migrated to the draining lymph node to become the most abundant skin-derived DC subset at 24 and 48 h after sensitization. None of these responses was observed in TSLPR-deficient mice. In contrast, TN DC numbers were not increased after treatment with the allergen house dust mite or the bacteria Escherichia coli and bacillus Calmette-Guérin, which increased other DC subsets. In vivo, treatment with rTSLP preferentially increased the numbers of TN DC in lymph nodes. In vitro, TN DC responded to rTSLP treatment with a higher level of STAT5 phosphorylation compared with other skin-derived DC subsets. The TN DC subset shared the morphology, phenotype, and developmental requirements of conventional DC, depending on FLT3 expression for their optimal development from bone marrow precursors, and CCR7 for migration to the draining lymph node. Thus, TN DC represent a dermal DC subset that should be considered in future studies of TSLP-dependent contact sensitization and skin immune responses.
Assuntos
Antígenos CD , Antígeno CD11b , Antígenos CD36 , Citocinas/imunologia , Células Dendríticas/imunologia , Dermatite Alérgica de Contato/imunologia , Derme/imunologia , Cadeias alfa de Integrinas , Animais , Antígenos de Dermatophagoides/imunologia , Antígenos de Dermatophagoides/toxicidade , Células Dendríticas/patologia , Dermatite Alérgica de Contato/patologia , Derme/patologia , Escherichia coli/imunologia , Linfonodos/imunologia , Linfonodos/patologia , Camundongos , Mycobacterium bovis/imunologia , Receptores CCR7/imunologia , Fator de Transcrição STAT5/imunologia , Linfopoietina do Estroma do TimoRESUMO
Screening a complete mouse phosphatase lentiviral shRNA library using high-throughput sequencing revealed several phosphatases that regulate CD4 T-cell differentiation. We concentrated on two lipid phosphatases, the myotubularin-related protein (MTMR)9 and -7. Silencing MTMR9 by shRNA or siRNA resulted in enhanced T-helper (Th)1 differentiation and increased Th1 protein kinase B (PKB)/AKT phosphorylation while silencing MTMR7 caused increased Th2 and Th17 differentiation and increased AKT phosphorylation in these cells. Irradiated mice reconstituted with MTMR9 shRNA-transduced bone marrow cells had an elevated proportion of T-box transcription factor T-bet expressors among their CD4 T cells. After adoptive transfer of naïve cells from such reconstituted mice, immunization resulted in a greater proportion of T-box transcription factor T-bet-expressing cells. Thus, myotubularin-related proteins have a role in controlling in vitro and in vivo Th-cell differentiation, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity.
Assuntos
Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linfócitos T/citologia , Animais , Diferenciação Celular , Perfilação da Expressão Gênica , Biblioteca Gênica , Inativação Gênica , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação , RNA Interferente Pequeno/metabolismo , Células Th17/citologia , Células Th2/citologiaRESUMO
CD4(+) T-helper (Th) cells are a major cell population that play an important role in governing acquired immune responses to a variety of foreign antigens as well as inducing some types of autoimmune diseases. There are at least four distinct Th cell subsets (Th1, Th2, Th17, and inducible T-regulatory cells), each of which has specialized functions to control immune responses. Each of these cell types emerge from naive CD4(+) T cells after encounter with foreign antigens presented by dendritic cells (DCs). Each Th cell subset expresses a unique set of transcription factors and produces hallmark cytokines. Both T-cell receptor (TCR)-mediated stimulation and the cytokine environment created by activated CD4(+) T cells themselves, by 'partner' DCs, and/or other cell types during the course of differentiation, play an important role in the fate decisions toward distinct Th subsets. Here, we review how TCR-mediated signals in collaboration with the cytokine environment influence the fate decisions of naive CD4(+) T cells toward distinct Th subsets at the early stages of activation. We also discuss the roles of TCR-proximal signaling intermediates and of the Notch pathway in regulating the differentiation to distinct Th phenotypes.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Transdução de Sinais/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular , Citocinas/biossíntese , Citocinas/imunologia , Células Dendríticas/citologia , Regulação da Expressão Gênica/imunologia , Humanos , Ativação Linfocitária , Camundongos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/imunologia , Receptores Notch/genética , Receptores Notch/imunologia , Subpopulações de Linfócitos T/citologia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologiaRESUMO
T-bet is a critical transcription factor for T helper 1 (Th1) cell differentiation. To study the regulation and functions of T-bet, we developed a T-bet-ZsGreen reporter mouse strain. We determined that interleukin-12 (IL-12) and interferon-γ (IFN-γ) were redundant in inducing T-bet in mice infected with Toxoplasma gondii and that T-bet did not contribute to its own expression when induced by IL-12 and IFN-γ. By contrast, T-bet and the transcription factor Stat4 were critical for IFN-γ production whereas IFN-γ signaling was dispensable for inducing IFN-γ. Loss of T-bet resulted in activation of an endogenous program driving Th2 cell differentiation in cells expressing T-bet-ZsGreen. Genome-wide analyses indicated that T-bet directly induced many Th1 cell-related genes but indirectly suppressed Th2 cell-related genes. Our study revealed redundancy and synergy among several Th1 cell-inducing pathways in regulating the expression of T-bet and IFN-γ, and a critical role of T-bet in suppressing an endogenous Th2 cell-associated program.
Assuntos
Transdução de Sinais , Proteínas com Domínio T/imunologia , Células Th2/imunologia , Animais , Diferenciação Celular , Fator de Transcrição GATA3/imunologia , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-4/imunologia , Camundongos , Camundongos Knockout , Fator de Transcrição STAT4/deficiência , Fator de Transcrição STAT4/imunologia , Proteínas com Domínio T/deficiência , Células Th1/imunologia , Células Th2/citologia , Toxoplasma/imunologia , Toxoplasmose/imunologiaRESUMO
Naive CD4(+) T cells undergo massive proliferation and differentiation into at least four distinct helper T cell subsets after recognition of foreign antigen-derived peptides presented by dendritic cells. Each helper T cell subset expresses a distinct set of genes that encode unique transcription factor(s), as well as hallmark cytokines. The cytokine environment created by activated CD4(+) T cells, dendritic cells and/or other cell types during the course of differentiation is a major determinant for the helper T cell fate. This Review focuses on the role of cytokines of the common γ-chain (γ(c)) family in the determination of the effector helper T cell phenotype that naive CD4(+) T cells adopt after being activated and in the function of these helper T cells.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Citocinas/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Antígenos/imunologia , Diferenciação Celular/imunologia , Citocinas/farmacologia , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Regulação da Expressão Gênica/imunologia , Humanos , Ativação Linfocitária/imunologia , Camundongos , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/imunologiaRESUMO
Naïve CD4(+) T cells undergo massive cell proliferation upon encountering their cognate ligand. This proliferation depends upon appropriate cues from the antigen-presenting cells that have processed the antigen and present the peptide to the T cells, and requires the establishment of a cytokine environment that can support such proliferation. Expansion of antigen-specific CD4(+) T cells needs to be coupled with differentiation into one of several effector/regulatory phenotypes if the priming event is to result in cells that can initially act to control the particular pathogen that elicited the response, and later to serve as memory cells to insure an appropriate response upon reintroduction of the pathogen. Here, we discuss the initiation of T helper lineage commitment, the positive feedback regulation by the cytokine environment to enhance and stabilize the differentiation into distinct T helper subsets, and the biological significance of CD4(+) T cell plasticity and long-term CD4(+) T cell memory.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Memória Imunológica , Linfócitos T CD4-Positivos/citologia , Diferenciação Celular/imunologia , Proliferação de Células , Retroalimentação Fisiológica , Fator de Transcrição GATA3/genética , Fator de Transcrição GATA3/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologiaRESUMO
CD4 T cells play critical roles in mediating adaptive immunity to a variety of pathogens. They are also involved in autoimmunity, asthma, and allergic responses as well as in tumor immunity. During TCR activation in a particular cytokine milieu, naive CD4 T cells may differentiate into one of several lineages of T helper (Th) cells, including Th1, Th2, Th17, and iTreg, as defined by their pattern of cytokine production and function. In this review, we summarize the discovery, functions, and relationships among Th cells; the cytokine and signaling requirements for their development; the networks of transcription factors involved in their differentiation; the epigenetic regulation of their key cytokines and transcription factors; and human diseases involving defective CD4 T cell differentiation.
Assuntos
Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular , Animais , Linfócitos T CD4-Positivos/metabolismo , Linhagem da Célula , Citocinas/genética , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Transdução de Sinais , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismoRESUMO
Tpl2 (Tumor progression locus 2), also known as Cot/MAP3K8, is a hematopoietically expressed serine-threonine kinase. Tpl2 is known to have critical functions in innate immunity in regulating tumor necrosis factor-alpha, Toll-like receptor, and G protein-coupled receptor signaling; however, our understanding of its physiological role in T cells is limited. We investigated the potential roles of Tpl2 in T cells and found that it was induced by interleukin-12 in human and mouse T cells in a Stat4-dependent manner. Deficiency of Tpl2 was associated with impaired interferon (IFN)-gamma production. Accordingly, Tpl2(-/-) mice had impaired host defense against Toxoplasma gondii with reduced parasite clearance and decreased IFN-gamma production. Furthermore, reconstitution of Rag2(-/-) mice with Tpl2-deficient T cells followed by T. gondii infection recapitulated the IFN-gamma defect seen in the Tpl2-deficient mice, confirming a T cell-intrinsic defect. CD4(+) T cells isolated from Tpl2(-/-) mice showed poor induction of T-bet and failure to up-regulate Stat4 protein, which is associated with impaired TCR-dependent extracellular signal-regulated kinase activation. These data underscore the role of Tpl2 as a regulator of T helper cell lineage decisions and demonstrate that Tpl2 has an important functional role in the regulation of Th1 responses.
Assuntos
Interferon gama/imunologia , MAP Quinase Quinase Quinases/imunologia , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T/imunologia , Toxoplasma/imunologia , Animais , Linhagem da Célula , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Perfilação da Expressão Gênica , Humanos , Interleucina-12/imunologia , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Knockout , Análise em Microsséries , Proteínas Proto-Oncogênicas/genética , Fator de Transcrição STAT4/imunologia , Proteínas com Domínio T/imunologia , Células Th1/citologia , Células Th1/imunologia , Toxoplasmose Animal/imunologiaRESUMO
Interleukin (IL)-4 and -13 are related cytokines sharing functional receptors. IL-4 signals through the type I (IL-4Ralpha/common gamma-chain [gammac]) and the type II (IL-4Ralpha/-13Ralpha1) IL-4 receptors, whereas IL-13 utilizes only the type II receptor. In this study, we show that mouse bone marrow-derived macrophages and human and mouse monocytes showed a much greater sensitivity to IL-4 than to IL-13. Lack of functional gammac made these cells poorly responsive to IL-4, while retaining full responsiveness to IL-13. In mouse peritoneal macrophages, IL-4 potency exceeds that of IL-13, but lack of gammac had only a modest effect on IL-4 signaling. In contrast, IL-13 stimulated greater responses than IL-4 in fibroblasts. Using levels of receptor chain expression and known binding affinities, we modeled the assemblage of functional type I and II receptor complexes. The differential expression of IL-4Ralpha, IL-13Ralpha1, and gammac accounted for the distinct IL-4-IL-13 sensitivities of the various cell types. These findings provide an explanation for IL-13's principal function as an "effector" cytokine and IL-4's principal role as an "immunoregulatory" cytokine.