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1.
Nat Immunol ; 24(8): 1345-1357, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37400675

RESUMO

CD4+ T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8+ T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8+ T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4+ T cells is less well understood. We have characterized the murine CD4+ T cell response against a validated NeoAg (CLTCH129>Q) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTCH129>Q-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4+ T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8+ T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4+ T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-like CD4+ T cells results in lower PD-1 expression by CD8+ T cells in the tumor microenvironment and an increased frequency of PD-1+CD8+ T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4+ T cells in mediating antitumor immunity via providing help to CD8+ T cells and highlight their therapeutic potential in ACT.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Camundongos , Animais , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Imunoterapia Adotiva , Imunoterapia , Linfócitos T CD4-Positivos , Células-Tronco , Microambiente Tumoral
4.
Proc Natl Acad Sci U S A ; 119(10): e2113329119, 2022 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-35239442

RESUMO

SignificanceThe CD4+ Treg response following acute Listeria infection is heterogeneous and deploys two distinct modes of suppression coinciding with initial pathogen exposure and resolution of infection. This bimodal suppression of CD8+ T cells during priming and contraction is mediated by separate Treg lineages. These findings make a significant contribution to our understanding of the functional plasticity inherent within Tregs, which allows these cells to serve as a sensitive and dynamic cellular rheostat for the immune system to prevent autoimmune pathology in the face of inflammation attendant to acute infection, enable expansion of the pathogen-specific response needed to control the infection, and reestablish immune homeostasis after the threat has been contained.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Listeria monocytogenes/imunologia , Listeriose/imunologia , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/imunologia , Doença Aguda , Animais , Camundongos
5.
J Chem Inf Model ; 64(13): 5328-5343, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38635316

RESUMO

Research in the human genome sciences generates a substantial amount of genetic data for hundreds of thousands of individuals, which concomitantly increases the number of variants of unknown significance (VUS). Bioinformatic analyses can successfully reveal rare variants and variants with clear associations with disease-related phenotypes. These studies have had a significant impact on how clinical genetic screens are interpreted and how patients are stratified for treatment. There are few, if any, computational methods for variants comparable to biological activity predictions. To address this gap, we developed a machine learning method that uses protein three-dimensional structures from AlphaFold to predict how a variant will influence changes to a gene's downstream biological pathways. We trained state-of-the-art machine learning classifiers to predict which protein regions will most likely impact transcriptional activities of two proto-oncogenes, nuclear factor erythroid 2 (NFE2L2)-related factor 2 (NRF2) and c-Myc. We have identified classifiers that attain accuracies higher than 80%, which have allowed us to identify a set of key protein regions that lead to significant perturbations in c-Myc or NRF2 transcriptional pathway activities.


Assuntos
Aprendizado de Máquina , Humanos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/química , Conformação Proteica , Variação Genética , Genoma Humano , Modelos Moleculares , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/química , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biologia Computacional/métodos
6.
Nat Immunol ; 12(9): 908-13, 2011 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-21804558

RESUMO

Two competing theories have been put forward to explain the role of CD4(+) T cells in priming CD8(+) memory T cells: one proposes paracrine secretion of interleukin 2 (IL-2); the other proposes the activation of antigen-presenting cells (APCs) via the costimulatory molecule CD40 and its ligand CD40L. We investigated the requirement for IL-2 by the relevant three cell types in vivo and found that CD8(+) T cells, rather than CD4(+) T cells or dendritic cells (DCs), produced the IL-2 necessary for CD8(+) T cell memory. Il2(-/-) CD4(+) T cells were able to provide help only if their ability to transmit signals via CD40L was intact. Our findings reconcile contradictory elements implicit in each model noted above by showing that CD4(+) T cells activate APCs through a CD40L-dependent mechanism to enable autocrine production of IL-2 in CD8(+) memory T cells.


Assuntos
Comunicação Autócrina , Linfócitos T CD4-Positivos/imunologia , Antígenos CD40/imunologia , Ligante de CD40/imunologia , Linfócitos T CD8-Positivos , Células Dendríticas/imunologia , Memória Imunológica , Interleucina-2/imunologia , Animais , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Antígenos CD40/metabolismo , Ligante de CD40/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Proliferação de Células , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Interleucina-2/metabolismo , Listeria monocytogenes/crescimento & desenvolvimento , Listeriose/imunologia , Listeriose/microbiologia , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia
7.
Nat Immunol ; 12(11): 1086-95, 2011 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-21964609

RESUMO

The presence of immune memory at pathogen-entry sites is a prerequisite for protection. Nevertheless, the mechanisms that warrant immunity at peripheral interfaces are not understood. Here we show that the nonclassical major histocompatibility complex (MHC) class I molecule thymus leukemia antigen (TL), induced on dendritic cells interacting with CD8αα on activated CD8αß(+) T cells, mediated affinity-based selection of memory precursor cells. Furthermore, constitutive expression of TL on epithelial cells led to continued selection of mature CD8αß(+) memory T cells. The memory process driven by TL and CD8αα was essential for the generation of CD8αß(+) memory T cells in the intestine and the accumulation of highly antigen-sensitive CD8αß(+) memory T cells that form the first line of defense at the largest entry port for pathogens.


Assuntos
Células Dendríticas/metabolismo , Listeriose/imunologia , Glicoproteínas de Membrana/metabolismo , Células Precursoras de Linfócitos T/metabolismo , Linfócitos T/metabolismo , Animais , Antígenos/imunologia , Antígenos/metabolismo , Antígenos CD8/metabolismo , Diferenciação Celular , Seleção Clonal Mediada por Antígeno , Células Dendríticas/imunologia , Células Dendríticas/patologia , Imunidade nas Mucosas/genética , Memória Imunológica/genética , Ativação Linfocitária/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/patologia , Linfócitos T/imunologia , Linfócitos T/patologia , Transgenes/genética
8.
Nat Immunol ; 11(2): 114-20, 2010 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-20084069

RESUMO

Bcl-6 and Blimp-1 have recently been identified as key transcriptional regulators of effector and memory differentiation in CD4(+) T cells and CD8(+) T cells. Bcl-6 and Blimp-1 were previously known to be critical regulators of effector and memory differentiation of B lymphocytes. The new findings unexpectedly point to the Bcl-6 and Blimp-1 regulatory axis as a ubiquitous mechanism for controlling effector and memory lymphocyte differentiation and function. Bcl-6 and Blimp-1 are antagonistic transcription factors and can function as a self-reinforcing genetic switch for cell-fate decisions. However, their influences in different lymphocytes are complex. Here we review and examine the commonalities and differences in the functions of these transcription factors in CD4(+) follicular helper T(FH) lymphocytes, effector CD8(+) T lymphocytes and B lymphocytes.


Assuntos
Linfócitos B/citologia , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/imunologia , Proteínas Repressoras/imunologia , Linfócitos T/citologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Diferenciação Celular/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Humanos , Memória Imunológica/genética , Memória Imunológica/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Fator 1 de Ligação ao Domínio I Regulador Positivo , Proteínas Proto-Oncogênicas c-bcl-6 , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
Nature ; 520(7549): 692-6, 2015 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-25901682

RESUMO

Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient's tumour possesses a unique set of mutations ('the mutanome') that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient's individual tumour-specific mutations. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4(+) T cells. Vaccination with such CD4(+) immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4(+) T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo-epitope target repertoire of cancers, enabling the effective targeting of every patient's tumour with vaccines produced 'just in time'.


Assuntos
Epitopos de Linfócito T/genética , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunoterapia/métodos , Melanoma Experimental/imunologia , Melanoma Experimental/terapia , Mutação/genética , Algoritmos , Animais , Linfócitos T CD4-Positivos/imunologia , Vacinas Anticâncer/genética , Vacinas Anticâncer/imunologia , Simulação por Computador , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Exoma/genética , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Melanoma Experimental/genética , Camundongos , Medicina de Precisão/métodos , Análise de Sequência de DNA , Análise de Sobrevida
11.
Immunity ; 34(2): 141-3, 2011 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-21349425

RESUMO

A new report in Immunity shows that, rather than driving the metabolic changes required for proliferation, Akt controls the gene expression programs that determine whether activated CD8+ T cells differentiate into memory or effector cells.

13.
J Transl Med ; 16(1): 207, 2018 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-30031393

RESUMO

Metastatic melanoma represents a challenging clinical situation and, until relatively recently, there was an absence of effective treatment options. However, in 2011, the advanced melanoma treatment landscape was revolutionised with the approval of the anti-cytotoxic T-lymphocyte-associated protein-4 checkpoint inhibitor ipilimumab and the selective BRAF kinase inhibitor vemurafenib, both of which significantly improved overall survival. Since then, availability of new immunotherapies, especially the anti-programmed death-1 checkpoint inhibitors, as well as other targeted therapies, have further improved outcomes for patients with advanced melanoma. Seven years on from the first approval of these novel therapies, evidence for the use of various immune-based and targeted approaches is continuing to increase at a rapid rate. Improved understanding of the tumour microenvironment and tumour immuno-evasion strategies has resulted in different approaches to target and harness the immune response. These new immune-based approaches offer the opportunity for various approaches with distinct modes of action being used in combination with one another, as well as combined with other treatment modalities such as targeted therapy, electrochemotherapy and surgery. The increasing number of treatment options that are now available has resulted in a growing need to identify which patients will derive most benefit from which treatments. Much research is now focused on the identification of biomarkers that can be utilised to help select patients for treatment. These and other recent advances in the management of melanoma were the focus of discussions at the third Melanoma Bridge meeting (30 November-2 December, 2017, Naples, Italy), which is summarised in this report.


Assuntos
Melanoma/patologia , Biomarcadores Tumorais/metabolismo , Ensaios Clínicos como Assunto , Humanos , Imunoterapia , Melanoma/imunologia , Modelos Biológicos , Biologia de Sistemas
16.
J Immunol ; 194(10): 4717-28, 2015 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-25833397

RESUMO

In health, long-lived plasma cells (LLPC) are essential for durable protective humoral immunity, and, conversely, in disease are a major source of pathogenic Abs in autoimmunity, graft rejection, and allergy. However, the molecular basis for their longevity is largely unknown. We have recently found that CD28 signaling in plasma cells (PC) is essential for sustaining Ab titers, by supporting the survival of LLPC, but not short-lived PC (SLPC). We now find that, unlike SLPC, CD28 activation in LLPC induces prosurvival downstream Vav signaling. Knockin mice with CD28 cytoplasmic tail mutations that abrogate Vav signaling (CD28-AYAA) had significantly fewer LLPC but unaffected SLPC numbers, whereas mice with mutations that abrogate PI3K signaling (CD28-Y170F) were indistinguishable from wild-type controls. This was consistent with the loss of CD28's prosurvival effect in LLPC from CD28-AYAA, but not CD28-Y170F, mice. Furthermore, the CD28 Vav motif in the B lineage was essential for the long-term maintenance of Ag-specific LLPC populations and Ab titers in vivo. Signaling downstream of the CD28 Vav motif induced previously undescribed transcriptional regulation of B lymphocyte-induced maturation protein-1, a key mediator of PC differentiation and maintenance. These findings suggest CD28 signaling in LLPC modulates the central B lymphocyte-induced maturation protein-1 transcriptional nexus involved in long-term survival and function.


Assuntos
Antígenos CD28/metabolismo , Plasmócitos/citologia , Plasmócitos/imunologia , Transdução de Sinais/imunologia , Fatores de Transcrição/biossíntese , Motivos de Aminoácidos , Animais , Formação de Anticorpos/imunologia , Western Blotting , Antígenos CD28/imunologia , Diferenciação Celular/imunologia , Sobrevivência Celular/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoprecipitação , Subpopulações de Linfócitos/citologia , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Plasmócitos/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo , Prolina , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Transcrição/imunologia , Regulação para Cima
18.
Immunol Cell Biol ; 93(2): 120-5, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25245112

RESUMO

The generation of CD8(+) T cells by vaccination represents an important goal for protective immunity to infectious pathogens. It is thus of utmost importance to understand the mechanisms involved in the generation of optimal CD8(+) T-cell responses. The forkhead box O (FoxO) family of transcription factors has a crucial role in cellular responses to environmental change. Among them, FoxO3 is critically involved in the regulation of cellular proliferation, apoptosis, metabolism and stress resistance to withdrawal of nutrients or cytokine growth factors. Since the role of FoxO3 has been poorly studied in the immune system, here we have evaluated its involvement in the CD8(+) T-cell response. We observe that CD8(+) T cells deficient for FoxO3 undergo a significantly greater primary expansion than their wild-type (WT) counterparts in response to both infectious (vaccinia virus) or non-infectious (non-replicating cellular vaccine) immunogens, resulting in a larger cohort of cells following contraction. These survivors, however, do not undergo a greater secondary response than WT. Taken together, our data show that FoxO3 is a negative regulator of the CD8(+) T-cell response, specifically during the primary expansion.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Fatores de Transcrição Forkhead/metabolismo , Memória Imunológica , Animais , Diferenciação Celular/imunologia , Proliferação de Células , Citocinas/biossíntese , Proteína Forkhead Box O3 , Contagem de Linfócitos , Camundongos Endogâmicos C57BL
19.
J Immunol ; 190(1): 174-83, 2013 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-23197258

RESUMO

After antigenic stimulation, CD8(+) T cells undergo clonal expansion and differentiation into CTLs that can mount a strong defense against intracellular pathogens and tumors. SWAP-70-like adapter of T cells (SLAT), also known as Def6, is a novel guanine nucleotide exchange factor for the Cdc42 GTPase and plays a role in CD4(+) T cell activation and Th cell differentiation by controlling Ca(2+)/NFAT signaling, but its requirement in CD8(+) T cell response has not been explored. Using a range of transgenic and knockout in vivo systems, we show that SLAT is required for efficient expansion of CD8(+) T cells during the primary response but is not necessary for CTL differentiation. The reduced clonal expansion observed in the absence of SLAT resulted from a CD8(+) T cell-intrinsic proliferation defect and a reduced IL-2-dependent cell survival. On a molecular level, we show that Def6 deficiency resulted in defective TCR/CD28-induced NFAT translocation to the nucleus in CD8(+) T cells. Constitutively active Cdc42 or NFAT1 mutants fully restored the impaired expansion of Def6(-/-) CD8(+) T cells. Taken together, these data describe a new and pivotal role of SLAT-mediated NFAT activation in CD8(+) T cells, providing new insight into the signaling pathways involved in CD8(+) T cell proliferation.


Assuntos
Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição NFATC/fisiologia , Proteínas Nucleares/fisiologia , Proteína cdc42 de Ligação ao GTP/fisiologia , Animais , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular/genética , Proliferação de Células , Células Clonais/citologia , Células Clonais/imunologia , Células Clonais/metabolismo , Testes Imunológicos de Citotoxicidade/métodos , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Fatores de Troca do Nucleotídeo Guanina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/deficiência , Proteínas Nucleares/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Proteína cdc42 de Ligação ao GTP/genética
20.
J Immunol ; 190(11): 5609-19, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23630347

RESUMO

A key goal of vaccine immunotherapy is the generation of long-term memory CD8(+) T cells capable of mediating immune surveillance. We discovered a novel intercellular pathway governing the development of potent memory CD8(+) T cell responses against cell-associated Ags that is mediated through cross-presentation by XCR1(+) dendritic cells (DCs). Generation of CD8(+) memory T cells against tumor cells pulsed with an invariant NKT cell ligand depended on cross-talk between XCR1(+) and plasmacytoid DCs that was regulated by IFN-α/IFN-αR signals. IFN-α production by plasmacytoid DCs was stimulated by an OX40 signal from the invariant NKT cells, as well as an HMGB1 signal from the dying tumor cells. These findings reveal a previously unknown pathway of intercellular collaboration for the generation of tumor-specific CD8(+) memory T cells that can be exploited for strategic vaccination in the setting of tumor immunotherapy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Comunicação Celular/imunologia , Células Dendríticas/imunologia , Memória Imunológica , Células T Matadoras Naturais/imunologia , Animais , Linhagem Celular Tumoral , Quimiotaxia/imunologia , Células Dendríticas/metabolismo , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interleucina-12/biossíntese , Ligantes , Camundongos , Neoplasias/imunologia , Transdução de Sinais
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