Hobit confers tissue-dependent programs to type 1 innate lymphoid cells

2021 ◽  
Vol 118 (50) ◽  
pp. e2117965118
Author(s):  
Kentaro Yomogida ◽  
Tarin M. Bigley ◽  
Tihana Trsan ◽  
Susan Gilfillan ◽  
Marina Cella ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Salivary Glands ◽  
Intestinal Mucosa ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Unique Cell ◽  
The Impact

Identification of type 1 innate lymphoid cells (ILC1s) has been problematic. The transcription factor Hobit encoded by Zfp683 has been proposed as a major driver of ILC1 programs. Using Zfp683 reporter mice, we showed that correlation of Hobit expression with ILC1s is tissue- and context-dependent. In liver and intestinal mucosa, Zfp683 expression correlated well with ILC1s; in salivary glands, Zfp683 was coexpressed with the natural killer (NK) master transcription factors Eomes and TCF1 in a unique cell population, which we call ILC1-like NK cells; during viral infection, Zfp683 was induced in conventional NK cells of spleen and liver. The impact of Zfp683 deletion on ILC1s and NK cells was also multifaceted, including a marked decrease in granzyme- and interferon-gamma (IFNγ)–producing ILC1s in the liver, slightly fewer ILC1s and more Eomes+ TCF1+ ILC1-like NK cells in salivary glands, and only reduced production of granzyme B by ILC1 in the intestinal mucosa. NK cell–mediated control of viral infection was unaffected. We conclude that Hobit has two major impacts on ILC1s: It sustains liver ILC1 numbers, while promoting ILC1 functional maturation in other tissues by controlling TCF1, Eomes, and granzyme expression.

scholarly journals Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 595
Author(s):  
Martina Molgora ◽  
Victor S. Cortez ◽  
Marco Colonna
Keyword(s):  
Nk Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Cell Function ◽  
Nk Cell ◽  
Tumor Therapy ◽  
Tumor Immunotherapy ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
The Impact

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models.

Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells

2017 ◽  
Vol 18 (9) ◽  
pp. 1004-1015 ◽  
Author(s):  
Yulong Gao ◽  
Fernando Souza-Fonseca-Guimaraes ◽  
Tobias Bald ◽  
Susanna S Ng ◽  
Arabella Young ◽  
...  
Keyword(s):  
Nk Cells ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells

scholarly journals Toxoplasma gondiiInfection Drives Conversion of NK Cells into ILC1s

2019 ◽  
Author(s):  
Eugene Park ◽  
Swapneel J. Patel ◽  
Qiuling Wang ◽  
Prabhakar S. Andhey ◽  
Konstantin Zaitsev ◽  
...  
Keyword(s):  
Steady State ◽  
Tumor Microenvironment ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Natural Killer ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Conversion ◽  
Ongoing Infection

AbstractInnate lymphoid cells (ILCs) were originally classified based on their cytokine profiles, placing natural killer (NK) cells and ILC1s together, but recent studies support their separation into different lineages at steady-state. However, tumors may induce NK cell conversion into ILC1-like cells that are limited to the tumor microenvironment and whether this conversion occurs beyond this environment remains unknown. Here we describeToxoplasma gondiiinfection converts NK cells into cells resembling steady-state ILC1s that are heterogeneous and distinct from both steady-state NK cells and ILC1s in uninfected mice. Most toxoplasma-induced ILC1s were Eomes-dependent, indicating that NK cells can give rise to Eomes−Tbet-dependent ILC1-like cells that circulate widely and persist independent of ongoing infection. Moreover, these changes appear permanent, as supported by epigenetic analyses. Thus, these studies markedly expand current concepts of NK cells, ILCs, and their potential conversion.

scholarly journals Tissue-Resident NK Cells: Development, Maturation, and Clinical Relevance

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1553 ◽  
Author(s):  
Elaheh Hashemi ◽  
Subramaniam Malarkannan
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Germ Line ◽  
Strong Support ◽  
Lymphoid Cells ◽  
Immune Functions ◽  
Effector Functions ◽  
Activating Receptors ◽  
Central Factors

Natural killer (NK) cells belong to type 1 innate lymphoid cells (ILC1) and are essential in killing infected or transformed cells. NK cells mediate their effector functions using non-clonotypic germ-line-encoded activation receptors. The utilization of non-polymorphic and conserved activating receptors promoted the conceptual dogma that NK cells are homogeneous with limited but focused immune functions. However, emerging studies reveal that NK cells are highly heterogeneous with divergent immune functions. A distinct combination of several activation and inhibitory receptors form a diverse array of NK cell subsets in both humans and mice. Importantly, one of the central factors that determine NK cell heterogeneity and their divergent functions is their tissue residency. Decades of studies provided strong support that NK cells develop in the bone marrow. However, evolving evidence supports the notion that NK cells also develop and differentiate in tissues. Here, we summarize the molecular basis, phenotypic signatures, and functions of tissue-resident NK cells and compare them with conventional NK cells.

scholarly journals NK cells and type 1 innate lymphoid cells: partners in host defense

2016 ◽  
Vol 17 (7) ◽  
pp. 758-764 ◽  
Author(s):  
Hergen Spits ◽  
Jochem H Bernink ◽  
Lewis Lanier
Keyword(s):  
Nk Cells ◽  
Host Defense ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells

scholarly journals Natural Killer Cells and Type 1 Innate Lymphoid Cells in Hepatocellular Carcinoma: Current Knowledge and Future Perspectives

2021 ◽  
Vol 22 (16) ◽  
pp. 9044
Author(s):  
Nicolas Jacquelot ◽  
Cyril Seillet ◽  
Fernando Souza-Fonseca-Guimaraes ◽  
Adrian G. Sacher ◽  
Gabrielle T. Belz ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Nk Cells ◽  
Cancer Cells ◽  
Natural Killer ◽  
Current Knowledge ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Great Promise ◽  
Wide Range

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.

scholarly journals Differential requirements for CD45 in NK-cell function reveal distinct roles for Syk-family kinases

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3087-3095 ◽  
Author(s):  
David G. T. Hesslein ◽  
Emil H. Palacios ◽  
Joseph C. Sun ◽  
Joshua N. Beilke ◽  
Susan R. Watson ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Function ◽  
Nk Cell ◽  
Ex Vivo ◽  
Tyrosine Phosphatase ◽  
Functional Difference ◽  
Cell Functions ◽  
Activation Motif ◽  
The Impact

AbstractThe protein tyrosine phosphatase CD45 is an important regulator of Src-family kinase activity. We found that in the absence of CD45, natural killer (NK) cells are defective in protecting the host from mouse cytomegalovirus infection. We show that although CD45 is necessary for all immunoreceptor tyrosine–based activation motif (ITAM)–specific NK-cell functions and processes such as degranulation, cytokine production, and expansion during viral infection, the impact of CD45 deficiency on ITAM signaling differs depending on the downstream function. CD45-deficient NK cells are normal in their response to inflammatory cytokines when administered ex vivo and in the context of viral infection. Syk and ζ chain–associated protein kinase 70 (Zap70) are thought to play redundant roles in transmitting ITAM signals in NK cells. We show that Syk, but not Zap70, controls the remaining CD45-independent, ITAM-specific NK-cell functions, demonstrating a functional difference between these 2 Syk-kinase family members in primary NK cells.

scholarly journals Interleukins 12 and 15 induce cytotoxicity and early NK-cell differentiation in type 3 innate lymphoid cells

2017 ◽  
Vol 1 (27) ◽  
pp. 2679-2691 ◽  
Author(s):  
Ana Raykova ◽  
Paolo Carrega ◽  
Frank M. Lehmann ◽  
Robert Ivanek ◽  
Vanessa Landtwing ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Nk Cells ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Human Type ◽  
Key Points ◽  
Nk Cell Differentiation ◽  
Cytokine Stimulation ◽  
Type 3

Key Points Human type 3 ILCs acquire features of early differentiated NK cells upon cytokine stimulation. IL-12 and IL-15–differentiated human ILC3s acquire cytotoxicity and kill leukemic targets.

scholarly journals Fingolimod Therapy in Multiple Sclerosis Leads to the Enrichment of a Subpopulation of Aged NK Cells

2021 ◽  
Author(s):  
Svenja C. Schwichtenberg ◽  
Anne Wisgalla ◽  
Maria Schroeder-Castagno ◽  
Cesar Alvarez-González ◽  
Stephan Schlickeiser ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Nk Cells ◽  
Clustering Algorithm ◽  
Nk Cell ◽  
Oral Treatment ◽  
Cell Activity ◽  
Cell Subset ◽  
Lymphoid Cells ◽  
Clinical Phase ◽  
The Impact

AbstractFingolimod is an approved oral treatment for relapsing–remitting multiple sclerosis (RRMS) that modulates agonistically the sphingosin-1-phosphate receptor (S1PR), inhibiting thereby the egress of lymphocytes from the lymph nodes. In this interventional prospective clinical phase IV trial, we longitudinally investigated the impact of fingolimod on frequencies of NK cell subpopulations by flow cytometry in 17 RRMS patients at baseline and 1, 3, 6, and 12 months after treatment initiation. Clinical outcome was assessed by the Expanded Disability Status Scale (EDSS) and annualized relapse rates (ARR). Over the study period, median EDSS remained stable from month 3 to month 12, and ARR decreased compared to ARR in the 24 months prior treatment. Treatment was paralleled by an increased frequency of circulating NK cells, due primarily to an increase in CD56dimCD94low mature NK cells, while the CD56bright fraction and CD127+ innate lymphoid cells (ILCs) decreased over time. An unsupervised clustering algorithm further revealed that a particular fraction of NK cells defined by the expression of CD56dimCD16++KIR+/−NKG2A−CD94−CCR7+/−CX3CR1+/−NKG2C−NKG2D+NKp46−DNAM1++CD127+ increased during treatment. This specific phenotype might reflect a status of aged, fully differentiated, and less functional NK cells. Our study confirms that fingolimod treatment affects both NK cells and ILC. In addition, our study suggests that treatment leads to the enrichment of a specific NK cell subset characterized by an aged phenotype. This might limit the anti-microbial and anti-tumour NK cell activity in fingolimod-treated patients.

scholarly journals c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Caroline Tizian ◽  
Annette Lahmann ◽  
Oliver Hölsken ◽  
Catalina Cosovanu ◽  
Michael Kofoed-Branzk ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Nk Cell ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Negative Regulator ◽  
Signature Genes ◽  
Group 3 ◽  
Differentiation Status ◽  
Type 3

RORγt+ group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)−17 and IL-22. However, CCR6- ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet+ CCR6- ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6- ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1β, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6- ILC3s.

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