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1.
Cell ; 187(16): 4144-4146, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121844

RESUMO

LAG-3 is the third immune checkpoint pathway successfully targeted for cancer therapy. Although ineffective as a monotherapy, combination of LAG-3 and PD-1 blockade improves survival from advanced melanoma. In this issue of Cell, two studies in mice and a human clinical trial provide insights on LAG-3 in immune regulation.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos , Proteína do Gene 3 de Ativação de Linfócitos , Linfócitos T CD8-Positivos/imunologia , Humanos , Animais , Camundongos , Antígenos CD/metabolismo , Antígenos CD/imunologia , Melanoma/imunologia , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/imunologia , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico
2.
Cell ; 187(16): 4355-4372.e22, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121848

RESUMO

Overcoming immune-mediated resistance to PD-1 blockade remains a major clinical challenge. Enhanced efficacy has been demonstrated in melanoma patients with combined nivolumab (anti-PD-1) and relatlimab (anti-LAG-3) treatment, the first in its class to be FDA approved. However, how these two inhibitory receptors synergize to hinder anti-tumor immunity remains unknown. Here, we show that CD8+ T cells deficient in both PD-1 and LAG-3, in contrast to CD8+ T cells lacking either receptor, mediate enhanced tumor clearance and long-term survival in mouse models of melanoma. PD-1- and LAG-3-deficient CD8+ T cells were transcriptionally distinct, with broad TCR clonality and enrichment of effector-like and interferon-responsive genes, resulting in enhanced IFN-γ release indicative of functionality. LAG-3 and PD-1 combined to drive T cell exhaustion, playing a dominant role in modulating TOX expression. Mechanistically, autocrine, cell-intrinsic IFN-γ signaling was required for PD-1- and LAG-3-deficient CD8+ T cells to enhance anti-tumor immunity, providing insight into how combinatorial targeting of LAG-3 and PD-1 enhances efficacy.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos , Interferon gama , Proteína do Gene 3 de Ativação de Linfócitos , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1 , Receptor de Morte Celular Programada 1/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Animais , Interferon gama/metabolismo , Camundongos , Antígenos CD/metabolismo , Comunicação Autócrina , Humanos , Melanoma/imunologia , Melanoma/tratamento farmacológico , Feminino , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Exaustão das Células T
3.
Cell ; 187(16): 4373-4388.e15, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121849

RESUMO

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.


Assuntos
Linfócitos T CD8-Positivos , Proteína do Gene 3 de Ativação de Linfócitos , Melanoma , Receptor de Morte Celular Programada 1 , Humanos , Antígenos CD/metabolismo , Antígenos CD/genética , Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Fatores de Transcrição de Zíper de Leucina Básica/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Citotoxicidade Imunológica , Proteínas de Grupo de Alta Mobilidade , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Proteína do Gene 3 de Ativação de Linfócitos/antagonistas & inibidores , Melanoma/imunologia , Melanoma/tratamento farmacológico , Melanoma/genética , Nivolumabe/uso terapêutico , Nivolumabe/farmacologia , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais
4.
Cell ; 187(16): 4336-4354.e19, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121847

RESUMO

Exhausted CD8 T (Tex) cells in chronic viral infection and cancer have sustained co-expression of inhibitory receptors (IRs). Tex cells can be reinvigorated by blocking IRs, such as PD-1, but synergistic reinvigoration and enhanced disease control can be achieved by co-targeting multiple IRs including PD-1 and LAG-3. To dissect the molecular changes intrinsic when these IR pathways are disrupted, we investigated the impact of loss of PD-1 and/or LAG-3 on Tex cells during chronic infection. These analyses revealed distinct roles of PD-1 and LAG-3 in regulating Tex cell proliferation and effector functions, respectively. Moreover, these studies identified an essential role for LAG-3 in sustaining TOX and Tex cell durability as well as a LAG-3-dependent circuit that generated a CD94/NKG2+ subset of Tex cells with enhanced cytotoxicity mediated by recognition of the stress ligand Qa-1b, with similar observations in humans. These analyses disentangle the non-redundant mechanisms of PD-1 and LAG-3 and their synergy in regulating Tex cells.


Assuntos
Antígenos CD , Linfócitos T CD8-Positivos , Antígenos de Histocompatibilidade Classe I , Proteína do Gene 3 de Ativação de Linfócitos , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Receptor de Morte Celular Programada 1 , Animais , Antígenos CD/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Subfamília D de Receptores Semelhantes a Lectina de Células NK/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismo , Camundongos Endogâmicos C57BL , Proteínas de Grupo de Alta Mobilidade/metabolismo , Proteínas de Grupo de Alta Mobilidade/genética , Citotoxicidade Imunológica , Proliferação de Células , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/imunologia
5.
Cell ; 187(15): 4078-4094.e21, 2024 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-38897196

RESUMO

Reversing CD8+ T cell dysfunction is crucial in treating chronic hepatitis B virus (HBV) infection, yet specific molecular targets remain unclear. Our study analyzed co-signaling receptors during hepatocellular priming and traced the trajectory and fate of dysfunctional HBV-specific CD8+ T cells. Early on, these cells upregulate PD-1, CTLA-4, LAG-3, OX40, 4-1BB, and ICOS. While blocking co-inhibitory receptors had minimal effect, activating 4-1BB and OX40 converted them into antiviral effectors. Prolonged stimulation led to a self-renewing, long-lived, heterogeneous population with a unique transcriptional profile. This includes dysfunctional progenitor/stem-like (TSL) cells and two distinct dysfunctional tissue-resident memory (TRM) populations. While 4-1BB expression is ubiquitously maintained, OX40 expression is limited to TSL. In chronic settings, only 4-1BB stimulation conferred antiviral activity. In HBeAg+ chronic patients, 4-1BB activation showed the highest potential to rejuvenate dysfunctional CD8+ T cells. Targeting all dysfunctional T cells, rather than only stem-like precursors, holds promise for treating chronic HBV infection.


Assuntos
Linfócitos T CD8-Positivos , Vírus da Hepatite B , Hepatite B Crônica , Humanos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Hepatite B Crônica/metabolismo , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais , Animais , Receptores OX40/metabolismo , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Antígenos CD/metabolismo
6.
Nat Immunol ; 25(8): 1355-1366, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39014161

RESUMO

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity; however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1-BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to mediate the γδTCR interaction; indeed, locking BTN2A1 and BTN3A1 together abrogated their interaction with γδTCR, supporting a model wherein the two γδTCR ligand-binding sites depend on accessibility to cryptic BTN epitopes. Our findings reveal a new paradigm in immune activation, whereby γδTCRs sense dual epitopes on BTN complexes.


Assuntos
Butirofilinas , Receptores de Antígenos de Linfócitos T gama-delta , Butirofilinas/metabolismo , Butirofilinas/imunologia , Butirofilinas/química , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Humanos , Ligação Proteica , Multimerização Proteica , Antígenos CD/metabolismo , Antígenos CD/imunologia , Antígenos CD/química , Linfócitos T/imunologia , Linfócitos T/metabolismo , Cristalografia por Raios X , Ativação Linfocitária/imunologia , Modelos Moleculares , Linfócitos Intraepiteliais/imunologia , Linfócitos Intraepiteliais/metabolismo
7.
Nat Immunol ; 25(5): 834-846, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38561495

RESUMO

Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.


Assuntos
Antígenos CD , Apirase , Cadeias alfa de Integrinas , Receptores de Antígenos de Linfócitos T , Transdução de Sinais , Animais , Humanos , Camundongos , Antígenos CD/metabolismo , Antígenos CD/imunologia , Linhagem Celular Tumoral , Citotoxicidade Imunológica , Cadeias alfa de Integrinas/metabolismo , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Linfócitos T Citotóxicos/imunologia
8.
Cell ; 184(26): 6243-6261.e27, 2021 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-34914922

RESUMO

COVID-19-induced "acute respiratory distress syndrome" (ARDS) is associated with prolonged respiratory failure and high mortality, but the mechanistic basis of lung injury remains incompletely understood. Here, we analyze pulmonary immune responses and lung pathology in two cohorts of patients with COVID-19 ARDS using functional single-cell genomics, immunohistology, and electron microscopy. We describe an accumulation of CD163-expressing monocyte-derived macrophages that acquired a profibrotic transcriptional phenotype during COVID-19 ARDS. Gene set enrichment and computational data integration revealed a significant similarity between COVID-19-associated macrophages and profibrotic macrophage populations identified in idiopathic pulmonary fibrosis. COVID-19 ARDS was associated with clinical, radiographic, histopathological, and ultrastructural hallmarks of pulmonary fibrosis. Exposure of human monocytes to SARS-CoV-2, but not influenza A virus or viral RNA analogs, was sufficient to induce a similar profibrotic phenotype in vitro. In conclusion, we demonstrate that SARS-CoV-2 triggers profibrotic macrophage responses and pronounced fibroproliferative ARDS.


Assuntos
COVID-19/patologia , COVID-19/virologia , Fibrose Pulmonar Idiopática/patologia , Fibrose Pulmonar Idiopática/virologia , Macrófagos/patologia , Macrófagos/virologia , SARS-CoV-2/fisiologia , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , COVID-19/diagnóstico por imagem , Comunicação Celular , Estudos de Coortes , Fibroblastos/patologia , Regulação da Expressão Gênica , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Fibrose Pulmonar Idiopática/genética , Células-Tronco Mesenquimais/patologia , Fenótipo , Proteoma/metabolismo , Receptores de Superfície Celular/metabolismo , Síndrome do Desconforto Respiratório/diagnóstico por imagem , Síndrome do Desconforto Respiratório/patologia , Síndrome do Desconforto Respiratório/virologia , Tomografia Computadorizada por Raios X , Transcrição Gênica
9.
Nat Immunol ; 24(2): 267-279, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36543958

RESUMO

CD8+ T cells are critical for elimination of cancer cells. Factors within the tumor microenvironment (TME) can drive these cells to a hypofunctional state known as exhaustion. The most terminally exhausted T (tTex) cells are resistant to checkpoint blockade immunotherapy and might instead limit immunotherapeutic efficacy. Here we show that intratumoral CD8+ tTex cells possess transcriptional features of CD4+Foxp3+ regulatory T cells and are similarly capable of directly suppressing T cell proliferation ex vivo. tTex cell suppression requires CD39, which generates immunosuppressive adenosine. Restricted deletion of CD39 in endogenous CD8+ T cells resulted in slowed tumor progression, improved immunotherapy responsiveness and enhanced infiltration of transferred tumor-specific T cells. CD39 is induced on tTex cells by tumor hypoxia, thus mitigation of hypoxia limits tTex suppression. Together, these data suggest tTex cells are an important regulatory population in cancer and strategies to limit their generation, reprogram their immunosuppressive state or remove them from the TME might potentiate immunotherapy.


Assuntos
Linfócitos T CD8-Positivos , Neoplasias , Humanos , Antígenos CD , Hipóxia , Neoplasias/terapia , Linfócitos T Reguladores , Microambiente Tumoral
10.
Nat Immunol ; 24(9): 1415-1422, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37488429

RESUMO

Lymphocyte activation gene 3 (LAG-3) is an inhibitory receptor that is highly expressed by exhausted T cells. LAG-3 is a promising immunotherapeutic target, with more than 20 LAG-3-targeting therapeutics in clinical trials and a fixed-dose combination of anti-LAG-3 and anti-PD-1 now approved to treat unresectable or metastatic melanoma. Although LAG-3 is widely recognized as a potent inhibitory receptor, important questions regarding its biology and mechanism of action remain. In this Perspective, we focus on gaps in the understanding of LAG-3 biology and discuss the five biggest topics of current debate and focus regarding LAG-3, including its ligands, signaling and mechanism of action, its cell-specific functions, its importance in different disease settings, and the development of novel therapeutics.


Assuntos
Proteína do Gene 3 de Ativação de Linfócitos , Melanoma , Humanos , Antígenos CD/genética , Linfócitos T , Melanoma/tratamento farmacológico
11.
Cell ; 180(4): 749-763.e13, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32059780

RESUMO

Immune responses in diverse tissue sites are critical for protective immunity and homeostasis. Here, we investigate how tissue localization regulates the development and function of human natural killer (NK) cells, innate lymphocytes important for anti-viral and tumor immunity. Integrating high-dimensional analysis of NK cells from blood, lymphoid organs, and mucosal tissue sites from 60 individuals, we identify tissue-specific patterns of NK cell subset distribution, maturation, and function maintained across age and between individuals. Mature and terminally differentiated NK cells with enhanced effector function predominate in blood, bone marrow, spleen, and lungs and exhibit shared transcriptional programs across sites. By contrast, precursor and immature NK cells with reduced effector capacity populate lymph nodes and intestines and exhibit tissue-resident signatures and site-specific adaptations. Together, our results reveal anatomic control of NK cell development and maintenance as tissue-resident populations, whereas mature, terminally differentiated subsets mediate immunosurveillance through diverse peripheral sites. VIDEO ABSTRACT.


Assuntos
Envelhecimento/imunologia , Células Matadoras Naturais/citologia , Linfopoese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Antígenos CD/metabolismo , Células Cultivadas , Criança , Feminino , Humanos , Imunidade Inata , Mucosa Intestinal/citologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/fisiologia , Pulmão/citologia , Linfonodos/citologia , Masculino , Pessoa de Meia-Idade , Baço/citologia
12.
Cell ; 182(3): 625-640.e24, 2020 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-32702313

RESUMO

The brain is a site of relative immune privilege. Although CD4 T cells have been reported in the central nervous system, their presence in the healthy brain remains controversial, and their function remains largely unknown. We used a combination of imaging, single cell, and surgical approaches to identify a CD69+ CD4 T cell population in both the mouse and human brain, distinct from circulating CD4 T cells. The brain-resident population was derived through in situ differentiation from activated circulatory cells and was shaped by self-antigen and the peripheral microbiome. Single-cell sequencing revealed that in the absence of murine CD4 T cells, resident microglia remained suspended between the fetal and adult states. This maturation defect resulted in excess immature neuronal synapses and behavioral abnormalities. These results illuminate a role for CD4 T cells in brain development and a potential interconnected dynamic between the evolution of the immunological and neurological systems. VIDEO ABSTRACT.


Assuntos
Encéfalo/citologia , Linfócitos T CD4-Positivos/metabolismo , Feto/citologia , Microglia/citologia , Microglia/metabolismo , Sinapses/metabolismo , Adulto , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Escala de Avaliação Comportamental , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Encéfalo/embriologia , Encéfalo/metabolismo , Criança , Feminino , Feto/embriologia , Humanos , Lectinas Tipo C/metabolismo , Pulmão/citologia , Pulmão/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neurogênese/genética , Parabiose , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Análise de Célula Única , Baço/citologia , Baço/metabolismo , Sinapses/imunologia , Transcriptoma
13.
Cell ; 183(5): 1383-1401.e19, 2020 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-33159858

RESUMO

Ebola virus (EBOV) causes epidemics with high mortality yet remains understudied due to the challenge of experimentation in high-containment and outbreak settings. Here, we used single-cell transcriptomics and CyTOF-based single-cell protein quantification to characterize peripheral immune cells during EBOV infection in rhesus monkeys. We obtained 100,000 transcriptomes and 15,000,000 protein profiles, finding that immature, proliferative monocyte-lineage cells with reduced antigen-presentation capacity replace conventional monocyte subsets, while lymphocytes upregulate apoptosis genes and decline in abundance. By quantifying intracellular viral RNA, we identify molecular determinants of tropism among circulating immune cells and examine temporal dynamics in viral and host gene expression. Within infected cells, EBOV downregulates STAT1 mRNA and interferon signaling, and it upregulates putative pro-viral genes (e.g., DYNLL1 and HSPA5), nominating pathways the virus manipulates for its replication. This study sheds light on EBOV tropism, replication dynamics, and elicited immune response and provides a framework for characterizing host-virus interactions under maximum containment.


Assuntos
Ebolavirus/fisiologia , Doença pelo Vírus Ebola/genética , Doença pelo Vírus Ebola/virologia , Interações Hospedeiro-Patógeno/genética , Análise de Célula Única , Animais , Antígenos CD/metabolismo , Biomarcadores/metabolismo , Efeito Espectador , Diferenciação Celular , Proliferação de Células , Citocinas/metabolismo , Ebolavirus/genética , Chaperona BiP do Retículo Endoplasmático , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Viral da Expressão Gênica , Doença pelo Vírus Ebola/imunologia , Doença pelo Vírus Ebola/patologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Interferons/genética , Interferons/metabolismo , Macaca mulatta , Macrófagos/metabolismo , Monócitos/metabolismo , Mielopoese , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Tempo , Transcriptoma/genética
14.
Nat Immunol ; 23(9): 1365-1378, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35999394

RESUMO

CD28 and CTLA-4 (CD152) play essential roles in regulating T cell immunity, balancing the activation and inhibition of T cell responses, respectively. Although both receptors share the same ligands, CD80 and CD86, the specific requirement for two distinct ligands remains obscure. In the present study, we demonstrate that, although CTLA-4 targets both CD80 and CD86 for destruction via transendocytosis, this process results in separate fates for CTLA-4 itself. In the presence of CD80, CTLA-4 remained ligand bound, and was ubiquitylated and trafficked via late endosomes and lysosomes. In contrast, in the presence of CD86, CTLA-4 detached in a pH-dependent manner and recycled back to the cell surface to permit further transendocytosis. Furthermore, we identified clinically relevant mutations that cause autoimmune disease, which selectively disrupted CD86 transendocytosis, by affecting either CTLA-4 recycling or CD86 binding. These observations provide a rationale for two distinct ligands and show that defects in CTLA-4-mediated transendocytosis of CD86 are associated with autoimmunity.


Assuntos
Antígenos CD , Antígenos CD28 , Antígenos CD/metabolismo , Antígenos de Diferenciação/metabolismo , Antígeno B7-1 , Antígeno B7-2/genética , Antígenos CD28/metabolismo , Antígeno CTLA-4/genética , Moléculas de Adesão Celular , Ligantes , Ativação Linfocitária
15.
Nat Immunol ; 23(7): 1031-1041, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35761082

RESUMO

The immune checkpoint receptor lymphocyte activation gene 3 protein (LAG3) inhibits T cell function upon binding to major histocompatibility complex class II (MHC class II) or fibrinogen-like protein 1 (FGL1). Despite the emergence of LAG3 as a target for next-generation immunotherapies, we have little information describing the molecular structure of the LAG3 protein or how it engages cellular ligands. Here we determined the structures of human and murine LAG3 ectodomains, revealing a dimeric assembly mediated by Ig domain 2. Epitope mapping indicates that a potent LAG3 antagonist antibody blocks interactions with MHC class II and FGL1 by binding to a flexible 'loop 2' region in LAG3 domain 1. We also defined the LAG3-FGL1 interface by mapping mutations onto structures of LAG3 and FGL1 and established that FGL1 cross-linking induces the formation of higher-order LAG3 oligomers. These insights can guide LAG3-based drug development and implicate ligand-mediated LAG3 clustering as a mechanism for disrupting T cell activation.


Assuntos
Antígenos CD/metabolismo , Ativação Linfocitária , Animais , Anticorpos , Fibrinogênio , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoterapia , Ligantes , Camundongos , Receptores Imunológicos , Proteína do Gene 3 de Ativação de Linfócitos
16.
Nat Immunol ; 23(5): 757-767, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35437325

RESUMO

LAG3 is an inhibitory receptor that is highly expressed on exhausted T cells. Although LAG3-targeting immunotherapeutics are currently in clinical trials, how LAG3 inhibits T cell function remains unclear. Here, we show that LAG3 moved to the immunological synapse and associated with the T cell receptor (TCR)-CD3 complex in CD4+ and CD8+ T cells, in the absence of binding to major histocompatibility complex class II-its canonical ligand. Mechanistically, a phylogenetically conserved, acidic, tandem glutamic acid-proline repeat in the LAG3 cytoplasmic tail lowered the pH at the immune synapse and caused dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor, which resulted in a loss of co-receptor-TCR signaling and limited T cell activation. These observations indicated that LAG3 functioned as a signal disruptor in a major histocompatibility complex class II-independent manner, and provide insight into the mechanism of action of LAG3-targeting immunotherapies.


Assuntos
Linfócitos T CD8-Positivos , Proteína Tirosina Quinase p56(lck) Linfócito-Específica , Antígenos CD/imunologia , Complexo CD3/imunologia , Antígenos CD8/metabolismo , Antígenos de Histocompatibilidade Classe II , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Proteína do Gene 3 de Ativação de Linfócitos
17.
Nat Immunol ; 23(5): 679-691, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35484408

RESUMO

Here we report the identification of human CD66b-CD64dimCD115- neutrophil-committed progenitor cells (NCPs) within the SSCloCD45dimCD34+ and CD34dim/- subsets in the bone marrow. NCPs were either CD45RA+ or CD45RA-, and in vitro experiments showed that CD45RA acquisition was not mandatory for their maturation process. NCPs exclusively generated human CD66b+ neutrophils in both in vitro differentiation and in vivo adoptive transfer experiments. Single-cell RNA-sequencing analysis indicated NCPs fell into four clusters, characterized by different maturation stages and distributed along two differentiation routes. One of the clusters was characterized by an interferon-stimulated gene signature, consistent with the reported expansion of peripheral mature neutrophil subsets that express interferon-stimulated genes in diseased individuals. Finally, comparison of transcriptomic and phenotypic profiles indicated NCPs represented earlier neutrophil precursors than the previously described early neutrophil progenitors (eNePs), proNeus and COVID-19 proNeus. Altogether, our data shed light on the very early phases of neutrophil ontogeny.


Assuntos
Antígenos CD , Medula Óssea , Moléculas de Adesão Celular , Diferenciação Celular , Neutrófilos , Receptor de Fator Estimulador de Colônias de Macrófagos , Receptores de IgG , Células da Medula Óssea , COVID-19 , Proteínas Ligadas por GPI , Humanos , Interferons , Neutrófilos/citologia
18.
Annu Rev Immunol ; 30: 1-22, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22136168

RESUMO

A properly functioning adaptive immune system signifies the best features of life. It is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges. Dendritic cells are required to explain how this remarkable system is energized and directed. I frame this article in terms of the major decisions that my colleagues and I have made in dendritic cell science and some of the guiding themes at the time the decisions were made. As a result of progress worldwide, there is now evidence of a central role for dendritic cells in initiating antigen-specific immunity and tolerance. The in vivo distribution and development of a previously unrecognized white cell lineage is better understood, as is the importance of dendritic cell maturation to link innate and adaptive immunity in response to many stimuli. Our current focus is on antigen uptake receptors on dendritic cells. These receptors enable experiments involving selective targeting of antigens in situ and new approaches to vaccine design in preclinical and clinical systems.


Assuntos
Alergia e Imunologia/tendências , Células Dendríticas/imunologia , Alergia e Imunologia/história , Animais , Antígenos CD/metabolismo , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , História do Século XX , História do Século XXI , Humanos , Tolerância Imunológica/imunologia , Imunidade Celular/imunologia , Lectinas Tipo C/metabolismo , Antígenos de Histocompatibilidade Menor , Modelos Animais , Receptores de Superfície Celular/metabolismo , Vacinas/imunologia
19.
Cell ; 176(1-2): 334-347.e12, 2019 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-30580966

RESUMO

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.


Assuntos
Antígenos CD/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , Animais , Antígenos CD/imunologia , Linhagem Celular , Fibrinogênio/imunologia , Fibrinogênio/metabolismo , Genes MHC da Classe II/genética , Genes MHC da Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Imunoterapia , Ligantes , Fígado/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias/genética , Neoplasias/imunologia , Linfócitos T Citotóxicos/imunologia , Proteína do Gene 3 de Ativação de Linfócitos
20.
Cell ; 177(4): 910-924.e22, 2019 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-30982595

RESUMO

The assembly of organized colonies is the earliest manifestation in the derivation or induction of pluripotency in vitro. However, the necessity and origin of this assemblance is unknown. Here, we identify human pluripotent founder cells (hPFCs) that initiate, as well as preserve and establish, pluripotent stem cell (PSC) cultures. PFCs are marked by N-cadherin expression (NCAD+) and reside exclusively at the colony boundary of primate PSCs. As demonstrated by functional analysis, hPFCs harbor the clonogenic capacity of PSC cultures and emerge prior to commitment events or phenotypes associated with pluripotent reprogramming. Comparative single-cell analysis with pre- and post-implantation primate embryos revealed hPFCs share hallmark properties with primitive endoderm (PrE) and can be regulated by non-canonical Wnt signaling. Uniquely informed by primate embryo organization in vivo, our study defines a subset of founder cells critical to the establishment pluripotent state.


Assuntos
Antígenos CD/metabolismo , Caderinas/metabolismo , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/metabolismo , Diferenciação Celular , Linhagem da Célula , Desenvolvimento Embrionário , Células-Tronco Embrionárias/metabolismo , Endoderma/metabolismo , Expressão Gênica/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Análise de Célula Única , Via de Sinalização Wnt
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