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1.
Immunol Cell Biol ; 99(9): 922-923, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34606127
2.
PLoS Pathog ; 17(10): e1009858, 2021 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-34618873

RESUMO

Autoimmune diseases are often treated by glucocorticoids and immunosuppressive drugs that could increase the risk for infection, which in turn deteriorate disease and cause mortality. Low-dose IL-2 (Ld-IL2) therapy emerges as a new treatment for a wide range of autoimmune diseases. To examine its influence on infection, we retrospectively studied 665 patients with systemic lupus erythematosus (SLE) including about one third receiving Ld-IL2 therapy, where Ld-IL2 therapy was found beneficial in reducing the incidence of infections. In line with this clinical observation, Ld-IL2 treatment accelerated viral clearance in mice infected with influenza A virus or lymphocytic choriomeningitis virus (LCMV). Noticeably, despite enhancing anti-viral immunity in LCMV infection, Ld-IL2 treatment exacerbated CD8+ T cell-mediated immunopathology. In summary, Ld-IL2 therapy reduced the risk of infections in SLE patients and enhanced the control of viral infection, but caution should be taken to avoid the potential risk of CD8+ T cell-mediated immunopathology in severe infections.

3.
J Immunol ; 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34599081

RESUMO

MHC class II (MHC II) Ag presentation by dendritic cells (DCs) is critical for CD4+ T cell immunity. Cell surface levels of MHC II loaded with peptide is controlled by ubiquitination. In this study, we have examined how MHC II ubiquitination impacts immunity using MHC IIKRKI/KI mice expressing mutant MHC II molecules that are unable to be ubiquitinated. Numbers of conventional DC (cDC) 1, cDC2 and plasmacytoid DCs were significantly reduced in MHC IIKRKI/KI spleen, with the remaining MHC IIKRKI/KI DCs expressing an altered surface phenotype. Whereas Ag uptake, endosomal pH, and cathepsin protease activity were unaltered, MHC IIKRKI/KI cDC1 produced increased inflammatory cytokines and possessed defects in Ag proteolysis. Immunization of MHC IIKRKI/KI mice identified impairments in MHC II and MHC class I presentation of soluble, cell-associated and/or DC-targeted OVA via mAb specific for DC surface receptor Clec9A (anti-Clec9A-OVA mAb). Reduced T cell responses and impaired CTL killing was observed in MHC IIKRKI/KI mice following immunization with cell-associated and anti-Clec9A-OVA. Immunization of MHC IIKRKI/KI mice failed to elicit follicular Th cell responses and generated barely detectable Ab to anti-Clec9A mAb-targeted Ag. In summary, MHC II ubiquitination in DCs impacts the homeostasis, phenotype, cytokine production, and Ag proteolysis by DCs with consequences for Ag presentation and T cell and Ab-mediated immunity.

4.
J Immunol ; 207(6): 1578-1590, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400523

RESUMO

In the Plasmodium berghei ANKA mouse model of malaria, accumulation of CD8+ T cells and infected RBCs in the brain promotes the development of experimental cerebral malaria (ECM). In this study, we used malaria-specific transgenic CD4+ and CD8+ T cells to track evolution of T cell immunity during the acute and memory phases of P. berghei ANKA infection. Using a combination of techniques, including intravital multiphoton and confocal microscopy and flow cytometric analysis, we showed that, shortly before onset of ECM, both CD4+ and CD8+ T cell populations exit the spleen and begin infiltrating the brain blood vessels. Although dominated by CD8+ T cells, a proportion of both T cell subsets enter the brain parenchyma, where they are largely associated with blood vessels. Intravital imaging shows these cells moving freely within the brain parenchyma. Near the onset of ECM, leakage of RBCs into areas of the brain can be seen, implicating severe damage. If mice are cured before ECM onset, brain infiltration by T cells still occurs, but ECM is prevented, allowing development of long-term resident memory T cell populations within the brain. This study shows that infiltration of malaria-specific T cells into the brain parenchyma is associated with cerebral immunopathology and the formation of brain-resident memory T cells. The consequences of these resident memory populations is unclear but raises concerns about pathology upon secondary infection.


Assuntos
Barreira Hematoencefálica/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Memória Imunológica , Malária Cerebral/imunologia , Plasmodium berghei/imunologia , Transferência Adotiva/métodos , Animais , Modelos Animais de Doenças , Feminino , Malária Cerebral/parasitologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parasitemia/imunologia , Baço/imunologia
5.
Nat Immunol ; 22(9): 1140-1151, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34426691

RESUMO

Tissue-resident memory T (TRM) cells are non-recirculating cells that exist throughout the body. Although TRM cells in various organs rely on common transcriptional networks to establish tissue residency, location-specific factors adapt these cells to their tissue of lodgment. Here we analyze TRM cell heterogeneity between organs and find that the different environments in which these cells differentiate dictate TRM cell function, durability and malleability. We find that unequal responsiveness to TGFß is a major driver of this diversity. Notably, dampened TGFß signaling results in CD103- TRM cells with increased proliferative potential, enhanced function and reduced longevity compared with their TGFß-responsive CD103+ TRM counterparts. Furthermore, whereas CD103- TRM cells readily modified their phenotype upon relocation, CD103+ TRM cells were comparatively resistant to transdifferentiation. Thus, despite common requirements for TRM cell development, tissue adaptation of these cells confers discrete functional properties such that TRM cells exist along a spectrum of differentiation potential that is governed by their local tissue microenvironment.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Diferenciação Celular/imunologia , Plasticidade Celular/imunologia , Microambiente Celular/imunologia , Memória Imunológica/imunologia , Animais , Antígenos CD/imunologia , Linfócitos T CD8-Positivos/citologia , Feminino , Cadeias alfa de Integrinas/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia , Fator de Crescimento Transformador beta1/metabolismo
6.
J Immunother Cancer ; 9(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34035114

RESUMO

Rapid advances in immunotherapy have identified adoptive cell transfer as one of the most promising approaches for the treatment of cancers. Large numbers of cancer reactive T lymphocytes can be generated ex vivo from patient blood by genetic modification to express chimeric antigen receptors (CAR) specific for tumor-associated antigens. CAR T cells can respond strongly against cancer cells, and adoptive transferred CAR T cells can induce dramatic responses against certain types of cancers. The ability of T cells to respond against disease depends on their ability to localize to sites, persist and exert functions, often in an immunosuppressive microenvironment, and these abilities are reflected in their phenotypes. There is currently intense interest in generating CAR T cells possessing the ideal phenotypes to confer optimal antitumor activity. In this article, we review T cell phenotypes for trafficking, persistence and function, and discuss how culture conditions and genetic makeups can be manipulated to achieve the ideal phenotypes for antitumor activities.

7.
Immunity ; 54(6): 1219-1230.e7, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915109

RESUMO

The sympathetic nervous system (SNS) controls various physiological functions via the neurotransmitter noradrenaline. Activation of the SNS in response to psychological or physical stress is frequently associated with weakened immunity. Here, we investigated how adrenoceptor signaling influences leukocyte behavior. Intravital two-photon imaging after injection of noradrenaline revealed transient inhibition of CD8+ and CD4+ T cell locomotion in tissues. Expression of ß-adrenergic receptor in hematopoietic cells was not required for NA-mediated inhibition of motility. Rather, chemogenetic activation of the SNS or treatment with adrenergic receptor agonists induced vasoconstriction and decreased local blood flow, resulting in abrupt hypoxia that triggered rapid calcium signaling in leukocytes and halted cell motility. Oxygen supplementation reversed these effects. Treatment with adrenergic receptor agonists impaired T cell responses induced in response to viral and parasitic infections, as well as anti-tumor responses. Thus, stimulation of the SNS impairs leukocyte mobility, providing a mechanistic understanding of the link between adrenergic receptors and compromised immunity.


Assuntos
Adrenérgicos/imunologia , Movimento Celular/imunologia , Imunidade/imunologia , Leucócitos/imunologia , Sistema Nervoso Simpático/imunologia , Animais , Sinalização do Cálcio/imunologia , Linhagem Celular Tumoral , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores Adrenérgicos/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
8.
Proc Natl Acad Sci U S A ; 118(17)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33875601

RESUMO

Leukocyte homing driven by the chemokine CCL21 is pivotal for adaptive immunity because it controls dendritic cell (DC) and T cell migration through CCR7. ACKR4 scavenges CCL21 and has been shown to play an essential role in DC trafficking at the steady state and during immune responses to tumors and cutaneous inflammation. However, the mechanism by which ACKR4 regulates peripheral DC migration is unknown, and the extent to which it regulates CCL21 in steady-state skin and lymph nodes (LNs) is contested. Specifically, our previous findings that CCL21 levels are increased in LNs of ACKR4-deficient mice [I. Comerford et al., Blood 116, 4130-4140 (2010)] were refuted [M. H. Ulvmar et al., Nat. Immunol. 15, 623-630 (2014)], and no differences in CCL21 levels in steady-state skin of ACKR4-deficient mice were reported despite compromised CCR7-dependent DC egress in these animals [S. A. Bryce et al., J. Immunol. 196, 3341-3353 (2016)]. Here, we resolve these issues and reveal that two forms of CCL21, full-length immobilized and cleaved soluble CCL21, exist in steady-state barrier tissues, and both are regulated by ACKR4. Without ACKR4, extracellular CCL21 gradients in barrier sites are saturated and nonfunctional, DCs cannot home directly to lymphatic vessels, and excess soluble CCL21 from peripheral tissues pollutes downstream LNs. The results identify the mechanism by which ACKR4 controls DC migration in barrier tissues and reveal a complex mode of CCL21 regulation in vivo, which enhances understanding of functional chemokine gradient formation.

9.
Nat Immunol ; 22(4): 434-448, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33649580

RESUMO

T cells dynamically interact with multiple, distinct cellular subsets to determine effector and memory differentiation. Here, we developed a platform to quantify cell location in three dimensions to determine the spatial requirements that direct T cell fate. After viral infection, we demonstrated that CD8+ effector T cell differentiation is associated with positioning at the lymph node periphery. This was instructed by CXCR3 signaling since, in its absence, T cells are confined to the lymph node center and alternatively differentiate into stem-like memory cell precursors. By mapping the cellular sources of CXCR3 ligands, we demonstrated that CXCL9 and CXCL10 are expressed by spatially distinct dendritic and stromal cell subsets. Unlike effector cells, retention of stem-like memory precursors in the paracortex is associated with CCR7 expression. Finally, we demonstrated that T cell location can be tuned, through deficiency in CXCL10 or type I interferon signaling, to promote effector or stem-like memory fates.


Assuntos
Infecções por Arenaviridae/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Diferenciação Celular , Quimiocina CXCL10/metabolismo , Quimiocina CXCL9/metabolismo , Memória Imunológica , Linfonodos/metabolismo , Células Precursoras de Linfócitos T/metabolismo , Receptores CXCR3/metabolismo , Animais , Infecções por Arenaviridae/genética , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/virologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Linhagem da Célula , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL9/genética , Quimiotaxia de Leucócito , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Interferon Tipo I/metabolismo , Ligantes , Linfonodos/imunologia , Linfonodos/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/patogenicidade , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Células Precursoras de Linfócitos T/imunologia , Células Precursoras de Linfócitos T/virologia , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Receptores CCR7/metabolismo , Receptores CXCR3/genética , Transdução de Sinais , Nicho de Células-Tronco , Células Estromais/imunologia , Células Estromais/metabolismo
10.
Nat Protoc ; 16(4): 1907-1935, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33627843

RESUMO

Multiphoton intravital imaging is essential for understanding cellular behavior and function in vivo. The adipose-rich environment of the mammary gland poses a unique challenge to in vivo microscopy due to light scattering that impedes high-resolution imaging. Here we provide a protocol for high-quality, six-color 3D intravital imaging of regions across the entire mouse mammary gland and associated tissues for several hours while maintaining tissue access for microdissection and labeling. An incision at the ventral midline and along the right hind leg creates a skin flap that is then secured to a raised platform skin side down. This allows for fluorescence-guided microdissection of connective tissue to provide unimpeded imaging of mammary ducts. A sealed imaging chamber over the skin flap creates a stable environment while maintaining access to large tissue regions for imaging with an upright microscope. We provide a strategy for imaging single cells and the tissue microenvironment utilizing multicolor Confetti lineage-tracing and additional dyes using custom-designed filters and sequential excitation with dual multiphoton lasers. Furthermore, we describe a strategy for simultaneous imaging and photomanipulation of single cells using the Olympus SIM scanner and provide steps for 3D video processing, visualization and high-dimensional analysis of single-cell behavior. We then provide steps for multiplexing intravital imaging with fixation, immunostaining, tissue clearing and 3D confocal imaging to associate cell behavior with protein expression. The skin-flap surgery and chamber preparation take 1.5 h, followed by up to 12 h of imaging. Applications range from basic filming in 1 d to 5 d for multiplexing and complex analysis.


Assuntos
Microscopia Intravital/métodos , Glândulas Mamárias Animais/citologia , Análise de Célula Única , Anestesia , Animais , Células Epiteliais/citologia , Feminino , Corantes Fluorescentes/química , Proteínas de Fluorescência Verde/metabolismo , Imageamento Tridimensional , Glândulas Mamárias Animais/cirurgia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Estromais/citologia
11.
Cell Rep ; 33(13): 108567, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33378682

RESUMO

Concurrent infection with multiple pathogens occurs frequently in individuals and can result in exacerbated infections and altered immunity. However, the impact of such coinfections on immune responses remains poorly understood. Here, we reveal that systemic infection results in an inflammation-induced suppression of local immunity. During localized infection or vaccination in barrier tissues including the skin or respiratory tract, concurrent systemic infection induces a type I interferon-dependent lymphopenia that impairs lymphocyte recruitment to the draining lymph node (dLN) and induces sequestration of lymphocytes in non-draining LN. This contributes to suppressed fibroblastic reticular cell and endothelial cell expansion and dLN remodeling and impairs induction of B cell responses and antibody production. Our data suggest that contemporaneous systemic inflammation constrains the induction of regional immunity.


Assuntos
Coinfecção/imunologia , Herpes Simples/imunologia , Inflamação/imunologia , Coriomeningite Linfocítica/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Tecido Linfoide/imunologia , Simplexvirus/imunologia , Animais , Formação de Anticorpos , Fibroblastos/imunologia , Herpes Simples/virologia , Interferon Tipo I/metabolismo , Linfonodos/imunologia , Linfonodos/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Coriomeningite Linfocítica/virologia , Tecido Linfoide/metabolismo , Linfopenia/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Células Estromais/imunologia , Células Estromais/metabolismo
12.
J Immunol ; 205(7): 1842-1856, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32839238

RESUMO

Follicular dendritic cells and macrophages have been strongly implicated in presentation of native Ag to B cells. This property has also occasionally been attributed to conventional dendritic cells (cDC) but is generally masked by their essential role in T cell priming. cDC can be divided into two main subsets, cDC1 and cDC2, with recent evidence suggesting that cDC2 are primarily responsible for initiating B cell and T follicular helper responses. This conclusion is, however, at odds with evidence that targeting Ag to Clec9A (DNGR1), expressed by cDC1, induces strong humoral responses. In this study, we reveal that murine cDC1 interact extensively with B cells at the border of B cell follicles and, when Ag is targeted to Clec9A, can display native Ag for B cell activation. This leads to efficient induction of humoral immunity. Our findings indicate that surface display of native Ag on cDC with access to both T and B cells is key to efficient humoral vaccination.


Assuntos
Linfócitos B/imunologia , Células Dendríticas/imunologia , Lectinas Tipo C/metabolismo , Receptores Imunológicos/metabolismo , Células Th1/imunologia , Células Th2/imunologia , Animais , Apresentação do Antígeno , Autoantígenos/imunologia , Autoantígenos/metabolismo , Diferenciação Celular , Células Cultivadas , Citocinas/metabolismo , Imunidade Humoral , Lectinas Tipo C/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Imunológicos/genética , Vacinação
13.
Nat Cell Biol ; 22(5): 546-558, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32341550

RESUMO

Macrophages are diverse immune cells that reside in all tissues. Although macrophages have been implicated in mammary-gland function, their diversity has not been fully addressed. By exploiting high-resolution three-dimensional imaging and flow cytometry, we identified a unique population of tissue-resident ductal macrophages that form a contiguous network between the luminal and basal layers of the epithelial tree throughout postnatal development. Ductal macrophages are long lived and constantly survey the epithelium through dendrite movement, revealed via advanced intravital imaging. Although initially originating from embryonic precursors, ductal macrophages derive from circulating monocytes as they expand during puberty. Moreover, they undergo proliferation in pregnancy to maintain complete coverage of the epithelium in lactation, when they are poised to phagocytose milk-producing cells post-lactation and facilitate remodelling. Interestingly, ductal macrophages strongly resemble mammary tumour macrophages and form a network that pervades the tumour. Thus, the mammary epithelium programs specialized resident macrophages in both physiological and tumorigenic contexts.


Assuntos
Células Epiteliais/fisiologia , Epitélio/fisiologia , Animais , Proliferação de Células/fisiologia , Feminino , Lactação/fisiologia , Macrófagos/fisiologia , Glândulas Mamárias Animais/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Monócitos/fisiologia , Fagocitose/fisiologia , Gravidez
16.
Front Immunol ; 10: 518, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31105685

RESUMO

Chemokines are a family of small protein cytokines that act as chemoattractants to migrating cells, in particular those of the immune system. They are categorized functionally as either homeostatic, constitutively produced by tissues for basal levels of cell migration, or inflammatory, where they are generated in association with a pathological inflammatory response. While the extravasation of leukocytes via blood vessels is a key step in cells entering the tissues, the lymphatic vessels also serve as a conduit for cells that are recruited and localized through chemoattractant gradients. Furthermore, the growth and remodeling of lymphatic vessels in pathologies is influenced by chemokines and their receptors expressed by lymphatic endothelial cells (LECs) in and around the pathological tissue. In this review we summarize the diverse role played by specific chemokines and their receptors in shaping the interaction of lymphatic vessels, immune cells, and other pathological cell types in physiology and disease.


Assuntos
Quimiocinas/imunologia , Vasos Linfáticos/imunologia , Animais , Citocinas/imunologia , Células Endoteliais/imunologia , Humanos , Inflamação/imunologia
17.
Cancer Cell ; 35(4): 618-632.e6, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30930118

RESUMO

Breast tumors are inherently heterogeneous, but the evolving cellular organization through neoplastic progression is poorly understood. Here we report a rapid, large-scale single-cell resolution 3D imaging protocol based on a one-step clearing agent that allows visualization of normal tissue architecture and entire tumors at cellular resolution. Imaging of multicolor lineage-tracing models of breast cancer targeted to either basal or luminal progenitor cells revealed profound clonal restriction during progression. Expression profiling of clones arising in Pten/Trp53-deficient tumors identified distinct molecular signatures. Strikingly, most clones harbored cells that had undergone an epithelial-to-mesenchymal transition, indicating widespread, inherent plasticity. Hence, an integrative pipeline that combines lineage tracing, 3D imaging, and clonal RNA sequencing technologies offers a comprehensive path for studying mechanisms underlying heterogeneity in whole tumors.


Assuntos
Neoplasias da Mama/patologia , Linhagem da Célula , Plasticidade Celular , Transição Epitelial-Mesenquimal , Imageamento Tridimensional , Microscopia Confocal , Análise de Célula Única/métodos , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Linhagem da Célula/genética , Plasticidade Celular/genética , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Heterogeneidade Genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos SCID , Camundongos Transgênicos , Análise de Sequência de RNA , Transcriptoma , Carga Tumoral
18.
Nat Immunol ; 20(5): 524-526, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30962592
19.
Immunol Rev ; 289(1): 115-128, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30977200

RESUMO

The initiation of T lymphocyte responses within secondary lymphoid organs involves interactions with different subsets of dendritic cells (DCs). Recent studies have revealed the complexity of microanatomical organization within lymphoid organs. Exactly how T cells and DCs locate each other and the type of cellular interactions required for optimal priming of effector and memory T cell responses are beginning to be unraveled. Here we review advances in our understanding of how T cell priming is choreographed during infections, highlight the importance of cell positioning in this process and discuss how a spectrum of cellular interactions shapes T cell activation and differentiation.


Assuntos
Células Dendríticas/imunologia , Infecções/imunologia , Tecido Linfoide/imunologia , Linfócitos T/imunologia , Animais , Apresentação do Antígeno , Comunicação Celular , Diferenciação Celular , Movimento Celular , Humanos , Ativação Linfocitária
20.
Nature ; 566(7745): E10, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30742076

RESUMO

Panel j was inadvertently labelled as panel k in the caption to Fig. 4. Similarly, 'Fig. 4k' should have been 'Fig. 4j' in the sentence beginning 'TNF-α-deficient gBT-I cells were…'. In addition, the surname of author Umaimainthan Palendira was misspelled 'Palendria'. These errors have been corrected online.

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