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1.
Int J Mol Sci ; 22(16)2021 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-34445750

RESUMO

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) are specific innate lymphoid cell subsets that are key for the detection and elimination of pathogens and cancer cells. In liver, while they share a number of characteristics, they differ in many features. These include their developmental pathways, tissue distribution, phenotype and functions. NK cells and ILC1 contribute to organ homeostasis through the production of key cytokines and chemokines and the elimination of potential harmful bacteria and viruses. In addition, they are equipped with a wide range of receptors, allowing them to detect "stressed cells' such as cancer cells. Our understanding of the role of innate lymphoid cells in hepatocellular carcinoma (HCC) is growing owing to the development of mouse models, the progress in immunotherapeutic treatment and the recent use of scRNA sequencing analyses. In this review, we summarize the current understanding of NK cells and ILC1 in hepatocellular carcinoma and discuss future strategies to take advantage of these innate immune cells in anti-tumor immunity. Immunotherapies hold great promise in HCC, and a better understanding of the role and function of NK cells and ILC1 in liver cancer could pave the way for new NK cell and/or ILC1-targeted treatment.


Assuntos
Carcinoma Hepatocelular/imunologia , Células Matadoras Naturais/fisiologia , Neoplasias Hepáticas/imunologia , Animais , Carcinoma Hepatocelular/terapia , Humanos , Imunoterapia , Fígado/imunologia , Neoplasias Hepáticas/terapia , Subpopulações de Linfócitos/fisiologia
2.
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
3.
Oncoimmunology ; 10(1): 1943168, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34239775

RESUMO

Immunity to melanoma is thought to be mainly mediated by adaptive immune cells. To what extent innate immunity, particularly innate lymphoid cells, drive the immune response and impact melanoma prognosis and therapeutic responsiveness is not well understood. In a recent article published in Nature Immunology, we uncovered a critical role that ILC2 play in the control of melanoma. Using both complementary mouse models and human samples, we showed that ILC2-derived granulocyte macrophage-colony stimulating factor (GM-CSF) drives eosinophil tumor recruitment and activation. We found that ILC2 express PD-1 which inhibits ILC2 effector function and impairs anti-tumor responses. We further demonstrated that the combination of IL-33 and anti-PD-1 blocking antibodies improved anti-tumor responses through the expansion of splenic and tumor-infiltrating ILC2 and eosinophils. These findings have revealed an essential mechanism involving ILC2 and eosinophils necessary for anti-melanoma immunity and immunotherapy responses.


Assuntos
Imunidade Inata , Melanoma , Eosinófilos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Linfócitos , Melanoma/tratamento farmacológico
4.
Nat Immunol ; 22(7): 851-864, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099918

RESUMO

Group 2 innate lymphoid cells (ILC2s) are essential to maintain tissue homeostasis. In cancer, ILC2s can harbor both pro-tumorigenic and anti-tumorigenic functions, but we know little about their underlying mechanisms or whether they could be clinically relevant or targeted to improve patient outcomes. Here, we found that high ILC2 infiltration in human melanoma was associated with a good clinical prognosis. ILC2s are critical producers of the cytokine granulocyte-macrophage colony-stimulating factor, which coordinates the recruitment and activation of eosinophils to enhance antitumor responses. Tumor-infiltrating ILC2s expressed programmed cell death protein-1, which limited their intratumoral accumulation, proliferation and antitumor effector functions. This inhibition could be overcome in vivo by combining interleukin-33-driven ILC2 activation with programmed cell death protein-1 blockade to significantly increase antitumor responses. Together, our results identified ILC2s as a critical immune cell type involved in melanoma immunity and revealed a potential synergistic approach to harness ILC2 function for antitumor immunotherapies.


Assuntos
Anticorpos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Interleucina-33/farmacologia , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Quimiotaxia de Leucócito/efeitos dos fármacos , Citotoxicidade Imunológica/efeitos dos fármacos , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Feminino , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo
5.
Mucosal Immunol ; 14(5): 1077-1087, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34083747

RESUMO

CD4+ T-helper 22 (Th22) cells are a phenotypically distinct lymphocyte subset that produces high levels of interleukin (IL)-22 without co-production of IL-17A. However, the developmental origin and lineage classification of Th22 cells, their interrelationship to Th17 cells, and potential for plasticity at sites of infection and inflammation remain largely undefined. An improved understanding of the mechanisms underpinning the outgrowth of Th22 cells will provide insights into their regulation during homeostasis, infection, and disease. To address this knowledge gap we generated 'IL-17A-fate-mapping IL-17A/IL-22 reporter transgenic mice' and show that Th22 cells develop in the gastrointestinal tract and lung during bacterial infection without transitioning via an Il17a-expressing intermediate, although in some compartments alternative transition pathways exist. Th22-cell development was not dependent on T-bet; however, this transcription factor functioned as a promiscuous T-cell-intrinsic regulator of IL-17A and IL-22 production, in addition to regulating the outgrowth, phenotypic stability, and plasticity of Th22 cells. Thus, we demonstrate that at sites of mucosal bacterial infection Th22 cells develop as a distinct lineage independently of Th17 cells; though both lineages exhibit bidirectional phenotypic flexibility within infected tissues and their draining lymph nodes, and that T-bet plays a critical regulatory role in Th22-cell function and identity.

6.
Trends Immunol ; 42(4): 273-275, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33674226

RESUMO

Irritable bowel syndrome often appears following gastrointestinal infection and is marked by diarrhea, dysbiosis, fever, and intestinal pain following eating. A recent study by Aguilera-Lizarraga et al. now demonstrates that a breakdown in intestinal immunotolerance sparks an inflammatory response to typically tolerated food antigens and causes visceral pain.


Assuntos
Disbiose , Síndrome do Intestino Irritável , Diarreia , Humanos , Dor
7.
Immunol Cell Biol ; 99(1): 65-83, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32748462

RESUMO

Type 2 innate lymphoid cells (ILC2s) are important producers of type 2 cytokines whose role in hematological cancers remains unclear. ILC2s are a heterogeneous population encompassing distinct subsets with different tissue localization and cytokine responsiveness. In this study, we investigated the role of bone marrow (BM) ILC2s and interleukin (IL)-33-stimulated ILC2s in multiple myeloma, a plasma cell malignancy that develops in the BM. We found that myeloma growth was associated with phenotypic and functional alterations of BM ILC2s, characterized by an increased expression of maturation markers and reduced cytokine response to IL-2/IL-33. We identified a population of KLRG1hi ILC2s that preferentially accumulated in the liver and spleen of Il2rg-/- Rag2-/- mice reconstituted with BM ILC2s. A similar population of KLRG1hi ILC2s was observed in the blood, liver and spleen of IL-33-treated wild-type mice. The presence of KLRG1hi ILC2s in ILC2-reconstituted Il2rg-/- Rag2-/- mice or in IL-33-treated wild-type mice was associated with increased eosinophil numbers but had no effect on myeloma progression. Interestingly, while decreased myeloma growth was observed following treatment of Rag-deficient mice with the type 1 cytokines IL-12 and IL-18, this protection was reversed when mice received a combined treatment of IL-33 together with IL-12 and IL-18. In summary, our data indicate that IL-33 treatment induces a population of circulating inflammatory KLRG1hi ILC2s and inhibits type 1 immunity against multiple myeloma. These results argue against therapeutic administration of IL-33 to myeloma patients.

8.
Allergy ; 76(3): 714-734, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32762040

RESUMO

The prevalence of chronic immune and metabolic disorders is increasing rapidly. In particular, inflammatory bowel diseases, obesity, diabetes, asthma and chronic obstructive pulmonary disease have become major healthcare and economic burdens worldwide. Recent advances in microbiome research have led to significant discoveries of associative links between alterations in the microbiome and health, as well as these chronic supposedly noncommunicable, immune/metabolic disorders. Importantly, the interplay between diet, microbiome and the mucous barrier in these diseases has gained significant attention. Diet modulates the mucous barrier via alterations in gut microbiota, resulting in either disease onset/exacerbation due to a "poor" diet or protection against disease with a "healthy" diet. In addition, many mucosa-associated disorders possess a specific gut microbiome fingerprint associated with the composition of the mucous barrier, which is further influenced by host-microbiome and inter-microbial interactions, dietary choices, microbe immigration and antimicrobials. Our review focuses on the interactions of diet (macronutrients and micronutrients), gut microbiota and mucous barriers (gastrointestinal and respiratory tract) and their importance in the onset and/or progression of major immune/metabolic disorders. We also highlight the key mechanisms that could be targeted therapeutically to prevent and/or treat these disorders.


Assuntos
Microbioma Gastrointestinal , Doenças do Sistema Imunitário , Microbiota , Dieta , Trato Gastrointestinal , Humanos
9.
Immunol Cell Biol ; 99(5): 542-551, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33295058

RESUMO

Innate lymphoid cells (ILCs) are resident in the lung and are involved in both the maintenance of homeostasis and the pathogenesis of respiratory diseases. In this study, murine lung ILCs were characterized using flow cytometry and the impact of mouse age, sex and strain were assessed. Lung ILCs were found as early as postnatal day 4 and numbers peaked at 2 weeks, and then decreased as the lung matured. During postnatal lung development, ILC expressed differential amounts of group 2 ILC (ILC2)-associated cell surface antigens including ST2, CD90.2 and ICOS. Using Il5venus Il13td-tomato dual reporter mice, neonates were found to have increased constitutive interleukin (IL)-13 expression compared with adult mice. Neonates and adults had similar ratios of IL-5+ CD45+ leukocytes; however, these cells were mostly composed of ILCs in neonates and T cells in adults. Sex-specific differences in ILC numbers were also observed, with females having greater numbers of lung ILCs than males in both neonatal and adult mice. Female lung ILCs also expressed higher levels of ICOS and decreased KLRG1. Mouse strain also impacted on lung ILCs with BALB/c mice having more ILCs in the lung and increased expression of ST2 and ICOS compared with C57BL/6J mice. Collectively, these data show that lung ILC numbers, cell surface antigen expression, IL-5 and IL-13 levels differed between neonatal and adult lung ILCs. In addition, cell surface antigens commonly used for ILC2 quantification, such as ST2, CD90.2 and ICOS, differ depending on age, sex and strain and these are important considerations for consistent universal identification of lung ILC2s.

10.
Nat Immunol ; 21(12): 1597-1610, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33046889

RESUMO

The dynamics of CD4+ T cell memory development remain to be examined at genome scale. In malaria-endemic regions, antimalarial chemoprevention protects long after its cessation and associates with effects on CD4+ T cells. We applied single-cell RNA sequencing and computational modelling to track memory development during Plasmodium infection and treatment. In the absence of central memory precursors, two trajectories developed as T helper 1 (TH1) and follicular helper T (TFH) transcriptomes contracted and partially coalesced over three weeks. Progeny of single clones populated TH1 and TFH trajectories, and fate-mapping suggested that there was minimal lineage plasticity. Relationships between TFH and central memory were revealed, with antimalarials modulating these responses and boosting TH1 recall. Finally, single-cell epigenomics confirmed that heterogeneity among effectors was partially reset in memory. Thus, the effector-to-memory transition in CD4+ T cells is gradual during malaria and is modulated by antiparasitic drugs. Graphical user interfaces are presented for examining gene-expression dynamics and gene-gene correlations ( http://haquelab.mdhs.unimelb.edu.au/cd4_memory/ ).


Assuntos
Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Memória Imunológica , Malária/imunologia , Plasmodium/imunologia , Transcriptoma , Transferência Adotiva , Animais , Antimaláricos/farmacologia , Biomarcadores , Cromatina/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Humanos , Malária/parasitologia , Malária/terapia , Camundongos , Plasmodium/efeitos dos fármacos
11.
Blood ; 136(26): 3004-3017, 2020 12 24.
Artigo em Inglês | MEDLINE | ID: mdl-32818230

RESUMO

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ). Exposure to fatty acids in the lymphoma environment potently suppressed NK cell effector response and cellular metabolism. NK cells from both diffuse large B-cell lymphoma patients and Eµ-myc B-cell lymphoma-bearing mice displayed reduced interferon-γ (IFN-γ) production. Activation of PPAR-γ partially restored mitochondrial membrane potential and IFN-γ production. Overall, our data indicate that increased lipid metabolism, while impairing their function, is a functional adaptation of NK cells to the fatty-acid rich lymphoma environment.


Assuntos
Células Matadoras Naturais/imunologia , Metabolismo dos Lipídeos/imunologia , Linfoma Difuso de Grandes Células B/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Interferon gama/genética , Interferon gama/imunologia , Células Matadoras Naturais/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Potencial da Membrana Mitocondrial/genética , Potencial da Membrana Mitocondrial/imunologia , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , PPAR gama/genética , PPAR gama/imunologia , Microambiente Tumoral/genética
12.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32695313

RESUMO

Tissue-resident immune cells stably localize in tissues largely independent of the circulatory system. While initial studies have focused on the recognition of CD8 + tissue-resident memory T (CD8 T RM) cells, it is now clear that numerous cell types such as CD4 + T cells, gd T cells, innate lymphoid cells and mucosal-associated invariant T (MAIT) cells form stable populations in tissues. They are enriched at the barrier surfaces and within non-lymphoid compartments. They provide an extensive immune network capable of sensing local perturbations of the body's homeostasis. This positioning enables immune cells to positively influence immune protection against infection and cancer but paradoxically also augment autoimmunity, allergy and chronic inflammatory diseases. Here, we highlight the recent studies across multiple lymphoid immune cell types that have emerged on this research topic and extend our understanding of this important cellular network. In addition, we highlight the areas that remain gaps in our knowledge of the regulation of these cells and how a deeper understanding may result in new ways to 'target' these cells to influence disease outcome and treatments.


Assuntos
Linfócitos , Autoimunidade , Imunidade Inata , Memória Imunológica , Linfócitos T
13.
Cancer Immunol Immunother ; 69(10): 1959-1972, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32388678

RESUMO

Cancer vaccine development has proven challenging with the exception of some virally induced cancers for which prophylactic vaccines exist. Currently, there is only one FDA approved vaccine for the treatment of prostate cancer and as such prostate cancer continues to present a significant unmet medical need. In this study, we examine the effectiveness of a therapeutic cancer vaccine that combines the ISCOMATRIX™ adjuvant (ISCOMATRIX) with the Toll-like receptor 3 agonist, polyinosinic-polycytidylic acid (Poly I:C), and Flt3L, FMS-like tyrosine kinase 3 ligand. We employed the TRAMP-C1 (transgenic adenocarcinoma of the mouse prostate) model of prostate cancer and the self-protein mPAP (prostatic acid phosphatase) as the tumor antigen. ISCOMATRIX™-mPAP-Poly I:C-Flt3L was delivered in a therapeutic prime-boost regime that was consistently able to achieve complete tumor regression in 60% of animals treated and these tumor-free animals were protected upon rechallenge. Investigations into the underlying immunological mechanisms contributing to the effectiveness of this vaccine identified that both innate and adaptive responses are elicited and required. NK cells, CD4+ T cells and interferon-γ were all found to be critical for tumor control while tumor infiltrating CD8+ T cells became disabled by an immunosuppressive microenvironment. There is potential for broader application of this cancer vaccine, as we have been able to demonstrate effectiveness in two additional cancer models; melanoma (B16-OVA) and a model of B cell lymphoma (Eµ-myc-GFP-OVA).


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Colesterol/administração & dosagem , Melanoma Experimental/imunologia , Fosfolipídeos/administração & dosagem , Neoplasias da Próstata/imunologia , Saponinas/administração & dosagem , Animais , Apoptose , Linfócitos T CD8-Positivos/efeitos dos fármacos , Proliferação de Células , Modelos Animais de Doenças , Combinação de Medicamentos , Humanos , Interferon gama/metabolismo , Masculino , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/imunologia , Poli I-C/administração & dosagem , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Células Tumorais Cultivadas , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
14.
Viral Immunol ; 33(3): 145-152, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32286183

RESUMO

Science is a tedious and painstaking business. Many discoveries are considered incremental, individually not necessarily earth shattering, but collectively providing the critical broad framework on which pivotal insights can emerge. Transformational discoveries spring from this knowledge legacy of others and spur a fervent discovery process, often driven by technological developments. The seminal discovery of major histocompatibility class restriction I (MHCI) and its role in antiviral infections by Doherty and Zinkernagel in 1974 was one such discovery-the key that unlocked the treasure chest to the rich tapestry of the diversity of the immune system. An army of researchers have teased apart the different elements of the immune response, which now brings us to a deeper understanding of immune memory and protective immunity. In this process, it has uncovered a multitude of cell types that bridge the innate and adaptive arms of the immune system-blurring the line between these two branches-and ultimately fortifying the development of long-term immune protection.


Assuntos
Imunidade Adaptativa , Alergia e Imunologia/história , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Viroses/imunologia , Animais , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Memória Imunológica , Camundongos , Linfócitos T/imunologia
16.
Immunol Cell Biol ; 98(4): 332-343, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31997396

RESUMO

Vaccination against γ-herpesviruses has proved difficult. CD4+ T cells are essential to contain infection, but how best to prime them and whether this can reduce viral loads remain unclear. To address these questions, we used ovalbumin (OVA) as a model antigen, delivering it with murine cytomegalovirus (MCMV) to protect mice against OVA-expressing murine herpesvirus-4 (MuHV-4). Membrane-associated OVA (mOVA) was more effective than soluble OVA, both to prime CD4+ T cells and as an effector target. It was also a better target than an OVA epitope limited to infected cells, suggesting that protective CD4+ T cells recognize infected cell debris rather than infected cells themselves. While MCMV-mOVA protected acutely against MuHV-4-mOVA, long-term protection was incomplete, even when OVA-specific CD8+ T cells and B cells were also primed. Thus, even optimized single-target vaccines may poorly reduce long-term γ-herpesvirus infections.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por Herpesviridae/imunologia , Vacinas contra Herpesvirus/imunologia , Imunogenicidade da Vacina/imunologia , Ovalbumina/imunologia , Rhadinovirus/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Infecções por Herpesviridae/prevenção & controle , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Rhadinovirus/genética , Fatores de Tempo , Vacinação
17.
Int Immunol ; 32(1): 27-38, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31504561

RESUMO

Immune responses against certain viruses are accompanied by auto-antibody production although the origin of these infection-associated auto-antibodies is unclear. Here, we report that murine γ-herpesvirus 68 (MHV68)-induced auto-antibodies are derived from polyreactive B cells in the germinal center (GC) through the activity of short-lived plasmablasts. The analysis of recombinant antibodies from MHV68-infected mice revealed that about 40% of IgG+ GC B cells were self-reactive, with about half of them being polyreactive. On the other hand, virion-reactive clones accounted for only a minor proportion of IgG+ GC B cells, half of which also reacted with self-antigens. The self-reactivity of most polyreactive clones was dependent on somatic hypermutation (SHM), but this was dispensable for the reactivity of virus mono-specific clones. Furthermore, both virus-mono-specific and polyreactive clones were selected to differentiate to B220lo CD138+ plasma cells (PCs). However, the representation of GC-derived polyreactive clones was reduced and that of virus-mono-specific clones was markedly increased in terminally differentiated PCs as compared to transient plasmablasts. Collectively, our findings demonstrate that, during acute MHV68 infection, self-reactive B cells are generated through SHM and selected for further differentiation to short-lived plasmablasts but not terminally differentiated PCs.


Assuntos
Linfócitos B/imunologia , Centro Germinativo/imunologia , Infecções por Herpesviridae/imunologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
18.
Nat Immunol ; 21(2): 168-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31873294

RESUMO

Group 3 innate lymphoid cell (ILC3)-mediated production of the cytokine interleukin-22 (IL-22) is critical for the maintenance of immune homeostasis in the gastrointestinal tract. Here, we find that the function of ILC3s is not constant across the day, but instead oscillates between active phases and resting phases. Coordinate responsiveness of ILC3s in the intestine depended on the food-induced expression of the neuropeptide vasoactive intestinal peptide (VIP). Intestinal ILC3s had high expression of the G protein-coupled receptor vasoactive intestinal peptide receptor 2 (VIPR2), and activation by VIP markedly enhanced the production of IL-22 and the barrier function of the epithelium. Conversely, deficiency in signaling through VIPR2 led to impaired production of IL-22 by ILC3s and increased susceptibility to inflammation-induced gut injury. Thus, intrinsic cellular rhythms acted in synergy with the cyclic patterns of food intake to drive the production of IL-22 and synchronize protection of the intestinal epithelium through a VIP-VIPR2 pathway in ILC3s.


Assuntos
Imunidade nas Mucosas/imunologia , Subpopulações de Linfócitos/imunologia , Linfócitos/imunologia , Periodicidade , Peptídeo Intestinal Vasoativo/imunologia , Animais , Ingestão de Alimentos/imunologia , Imunidade Inata/imunologia , Subpopulações de Linfócitos/metabolismo , Linfócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo Intestinal Vasoativo/metabolismo
19.
Cell Rep ; 29(8): 2257-2269.e6, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31747599

RESUMO

Despite the key role that antibodies play in protection, the cellular processes mediating the acquisition of humoral immunity against malaria are not fully understood. Using an infection model of severe malaria, we find that germinal center (GC) B cells upregulate the transcription factor T-bet during infection. Molecular and cellular analyses reveal that T-bet in B cells is required not only for IgG2c switching but also favors commitment of B cells to the dark zone of the GC. T-bet was found to regulate the expression of Rgs13 and CXCR3, both of which contribute to the impaired GC polarization observed in the absence of T-bet, resulting in reduced IghV gene mutations and lower antibody avidity. These results demonstrate that T-bet modulates GC dynamics, thereby promoting the differentiation of B cells with increased affinity for antigen.


Assuntos
Linfócitos B/metabolismo , Centro Germinativo/citologia , Centro Germinativo/metabolismo , Malária/metabolismo , Proteínas com Domínio T/metabolismo , Animais , Afinidade de Anticorpos/genética , Afinidade de Anticorpos/fisiologia , Malária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Proteínas RGS/genética , Proteínas RGS/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Proteínas com Domínio T/genética
20.
Cell Rep ; 28(7): 1758-1772.e4, 2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412245

RESUMO

Following infection, inflammatory cues upregulate core transcriptional programs to establish pathogen-specific protection. In viral infections, T follicular helper (TFH) cells express the prototypical T helper 1 transcription factor T-bet. Several studies have demonstrated essential but conflicting roles for T-bet in TFH biology. Understanding the basis of this controversy is crucial, as modulation of T-bet expression instructs TFH differentiation and ultimately protective antibody responses. Comparing influenza and LCMV viral infections, we demonstrate that the role of T-bet is contingent on the environmental setting of TFH differentiation, IL-2 signaling, and T cell competition. Furthermore, we demonstrate that T-bet expression by either TFH or GC B cells independently drives antibody isotype class switching. Specifically, T cell-specific loss of T-bet promotes IgG1, whereas B cell-specific loss of T-bet inhibits IgG2a/c switching. Combined, this work highlights that the context-dependent induction of T-bet instructs the development of protective, neutralizing antibodies following viral infection or vaccination.


Assuntos
Formação de Anticorpos/imunologia , Diferenciação Celular , Centro Germinativo/imunologia , Vírus da Coriomeningite Linfocítica/imunologia , Orthomyxoviridae/imunologia , Proteínas com Domínio T/fisiologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Anticorpos Antivirais/imunologia , Infecções por Arenaviridae/imunologia , Infecções por Arenaviridae/metabolismo , Infecções por Arenaviridae/virologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/virologia , Feminino , Centro Germinativo/metabolismo , Centro Germinativo/virologia , Imunoglobulina G/metabolismo , Ativação Linfocitária , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/metabolismo , Coriomeningite Linfocítica/virologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções por Orthomyxoviridae/imunologia , Infecções por Orthomyxoviridae/metabolismo , Infecções por Orthomyxoviridae/virologia , Transdução de Sinais , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/virologia
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