IL-23 and IL-2 activation of STAT5 is required for optimal IL-22 production in ILC3s during colitis

2020 ◽  
Vol 5 (46) ◽  
pp. eaav1080 ◽  
Author(s):  
David Bauché ◽  
Barbara Joyce-Shaikh ◽  
Julie Fong ◽  
Alejandro V. Villarino ◽  
Karin S. Ku ◽  
...  
Keyword(s):  
Immune Cells ◽  
Interleukin 2 ◽  
Disease Process ◽  
Genetic Alterations ◽  
Lymphoid Cells ◽  
Nucleotide Polymorphisms ◽  
Stat Proteins ◽  
Increased Risk ◽  
Promoter Dna ◽  
And Function

Signal transducer and activator of transcription (STAT) proteins have critical roles in the development and function of immune cells. STAT signaling is often dysregulated in patients with inflammatory bowel disease (IBD), suggesting the importance of STAT regulation during the disease process. Moreover, genetic alterations in STAT3 and STAT5 (e.g., deletions, mutations, and single-nucleotide polymorphisms) are associated with an increased risk for IBD. In this study, we elucidated the precise roles of STAT5 signaling in group 3 innate lymphoid cells (ILC3s), a key subset of immune cells involved in the maintenance of gut barrier integrity. We show that mice lacking either STAT5a or STAT5b are more susceptible to Citrobacter rodentium–mediated colitis and that interleukin-2 (IL-2)– and IL-23–induced STAT5 drives IL-22 production in both mouse and human colonic lamina propria ILC3s. Mechanistically, IL-23 induces a STAT3-STAT5 complex that binds IL-22 promoter DNA elements in ILC3s. Our data suggest that STAT5a/b signaling in ILC3s maintains gut epithelial integrity during pathogen-induced intestinal disease.

scholarly journals Biology and pathology of the uterine microenvironment and its natural killer cells

2021 ◽  
Author(s):  
Fuyan Wang ◽  
Anita Ellen Qualls ◽  
Laia Marques-Fernandez ◽  
Francesco Colucci
Keyword(s):  
Natural Killer ◽  
Fetal Growth ◽  
Immune Cells ◽  
Smooth Muscle Actin ◽  
Lymphoid Cells ◽  
Unk Cells ◽  
New Frontier ◽  
Uterine Mucosa ◽  
Blastocyst Implantation ◽  
And Function

AbstractTissues are the new frontier of discoveries in immunology. Cells of the immune system are an integral part of tissue physiology and immunity. Determining how immune cells inhabit, housekeep, and defend gut, lung, brain, liver, uterus, and other organs helps revealing the intimate details of tissue physiology and may offer new therapeutic targets to treat pathologies. The uterine microenvironment modulates the development and function of innate lymphoid cells [ILC, largely represented by natural killer (NK) cells], macrophages, T cells, and dendritic cells. These immune cells, in turn, contribute to tissue homeostasis. Regulated by ovarian hormones, the human uterine mucosa (endometrium) undergoes ~400 monthly cycles of breakdown and regeneration from menarche to menopause, with its fibroblasts, glands, blood vessels, and immune cells remodeling the tissue into the transient decidua. Even more transformative changes occur upon blastocyst implantation. Before the placenta is formed, the endometrial glands feed the embryo by histiotrophic nutrition while the uterine spiral arteries are stripped of their endothelial layer and smooth muscle actin. This arterial remodeling is carried out by invading fetal trophoblast and maternal immune cells, chiefly uterine NK (uNK) cells, which also assist fetal growth. The transformed arteries no longer respond to maternal stimuli and meet the increasing demands of the growing fetus. This review focuses on how the everchanging uterine microenvironment affects uNK cells and how uNK cells regulate homeostasis of the decidua, placenta development, and fetal growth. Determining these pathways will help understand the causes of major pregnancy complications.

scholarly journals Long Noncoding RNA in Myeloid and Lymphoid Cell Differentiation, Polarization and Function

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 269 ◽  
Author(s):  
Imran Ahmad ◽  
Araceli Valverde ◽  
Fayek Ahmad ◽  
Afsar Raza Naqvi
Keyword(s):  
Cell Differentiation ◽  
Immune Cells ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Immune Cell ◽  
Lymphoid Cells ◽  
Tissue Cell ◽  
Specific Expression ◽  
And Function

Long noncoding RNA (lncRNA) are a class of endogenous, non-protein coding RNAs that are increasingly being associated with various cellular functions and diseases. Yet, despite their ubiquity and abundance, only a minute fraction of these molecules has an assigned function. LncRNAs show tissue-, cell-, and developmental stage-specific expression, and are differentially expressed under physiological or pathological conditions. The role of lncRNAs in the lineage commitment of immune cells and shaping immune responses is becoming evident. Myeloid cells and lymphoid cells are two major classes of immune systems that work in concert to initiate and amplify innate and adaptive immunity in vertebrates. In this review, we provide mechanistic roles of lncRNA through which these noncoding RNAs can directly participate in the differentiation, polarization, and activation of myeloid (monocyte, macrophage, and dendritic cells) and lymphoid cells (T cells, B cells, and NK cells). While our knowledge on the role of lncRNA in immune cell differentiation and function has improved in the past decade, further studies are required to unravel the biological role of lncRNAs and identify novel mechanisms of lncRNA functions in immune cells. Harnessing the regulatory potential of lncRNAs can provide novel diagnostic and therapeutic targets in treating immune cell related diseases.

scholarly journals Emerging concepts and future challenges in innate lymphoid cell biology

2016 ◽  
Vol 213 (11) ◽  
pp. 2229-2248 ◽  
Author(s):  
Elia D. Tait Wojno ◽  
David Artis
Keyword(s):  
Immune Cells ◽  
Cell Biology ◽  
Critical Role ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Adaptive Immune Cells ◽  
New Findings ◽  
Basic Studies ◽  
New Treatments ◽  
And Function

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.

scholarly journals Regulated expression and function of CD122 (interleukin-2/interleukin- 15R-beta) during lymphoid development

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 190-201 ◽  
Author(s):  
T Reya ◽  
JA Yang-Snyder ◽  
EV Rothenberg ◽  
SR Carding
Keyword(s):  
B Cells ◽  
Fetal Liver ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
Lymphocyte Development ◽  
Hematopoietic Stem ◽  
Embryo Sections ◽  
And Function ◽  
Receptor Beta

To determine whether signaling via CD122 (interleukin-2 [IL-2]/IL-15 receptor beta-chain) plays a role in regulating the expansion and differentiation of lymphocyte precursors, we have characterized its expression and evaluated its ability to influence the activity of developing lymphoid cells. A significant fraction of Sca1+Lin- hematopoietic stem cells in day 12 fetal liver were found to be CD122+. CD122-mRNA+ and IL-2-mRNA+ cells were also localized in embryo sections within pharyngeal blood vessels adjacent to and surrounding the thymic analgen. This distribution is consistent with the migration of CD122+ progenitor cells from the liver to the developing thymus where a majority of Sca1+ intrathymic T-cell progenitors were CD122+. Analysis of CD122 expression in the day 12 fetal liver revealed that the majority of B220+ cells were CD122+. Furthermore, CD122 expression was restricted to the earliest B220+ cells (CD43+CD24-; prepro B cells; fraction A) that proliferate vigorously to IL-2 in the absence of any stromal cells, but not to IL-15. Consistent with a role for the IL-2/IL- 2R pathway in lymphocyte development is the progressive loss of B cells seen in IL-2-deficient mice. Together, these observations suggest that CD122 plays a role in regulating normal lymphocyte development in vivo.

scholarly journals Regulated expression and function of CD122 (interleukin-2/interleukin- 15R-beta) during lymphoid development

Blood ◽  
1996 ◽  
Vol 87 (1) ◽  
pp. 190-201 ◽  
Author(s):  
T Reya ◽  
JA Yang-Snyder ◽  
EV Rothenberg ◽  
SR Carding
Keyword(s):  
B Cells ◽  
Fetal Liver ◽  
Interleukin 2 ◽  
Lymphoid Cells ◽  
Lymphocyte Development ◽  
Hematopoietic Stem ◽  
Embryo Sections ◽  
And Function ◽  
Receptor Beta

Abstract To determine whether signaling via CD122 (interleukin-2 [IL-2]/IL-15 receptor beta-chain) plays a role in regulating the expansion and differentiation of lymphocyte precursors, we have characterized its expression and evaluated its ability to influence the activity of developing lymphoid cells. A significant fraction of Sca1+Lin- hematopoietic stem cells in day 12 fetal liver were found to be CD122+. CD122-mRNA+ and IL-2-mRNA+ cells were also localized in embryo sections within pharyngeal blood vessels adjacent to and surrounding the thymic analgen. This distribution is consistent with the migration of CD122+ progenitor cells from the liver to the developing thymus where a majority of Sca1+ intrathymic T-cell progenitors were CD122+. Analysis of CD122 expression in the day 12 fetal liver revealed that the majority of B220+ cells were CD122+. Furthermore, CD122 expression was restricted to the earliest B220+ cells (CD43+CD24-; prepro B cells; fraction A) that proliferate vigorously to IL-2 in the absence of any stromal cells, but not to IL-15. Consistent with a role for the IL-2/IL- 2R pathway in lymphocyte development is the progressive loss of B cells seen in IL-2-deficient mice. Together, these observations suggest that CD122 plays a role in regulating normal lymphocyte development in vivo.

scholarly journals Distinction between gamma c detection and function in YT lymphoid cells and in the granulocyte-macrophage colony-stimulating factor-responsive human myeloid cell line, Tf-1

Blood ◽  
1995 ◽  
Vol 86 (12) ◽  
pp. 4568-4578 ◽  
Author(s):  
NL Farner ◽  
SD Voss ◽  
TP Leary ◽  
J Gan ◽  
J Hakimi ◽  
...  
Keyword(s):  
Cell Line ◽  
Interleukin 2 ◽  
Cell Lineage ◽  
Myeloid Cell ◽  
Lymphoid Cells ◽  
Blood Monocytes ◽  
Cellular Environment ◽  
Myeloid Development ◽  
C Subunit ◽  
And Function

Peripheral blood monocytes respond to interleukin-2 (lL-2) and express the gamma common (gamma c) subunit of the lL-2 receptor (lL-2R) complex. However, the role of lL-2 in myeloid development has recently become of interest for several reasons, including the effect gamma c mutations may or may not have on myeloid development in patients with XSCID. Many studies of lL-2 function in the myeloid cell lineage have been performed on a murine background. To study gamma c expression and function in human myeloid precursors, we introduced the human myelomonocytic cell line, Tf-1, with a retroviral vector containing the human lL-2R beta subunit to create functional human intermediate lL-2R consisting of beta gamma c dimers. We have characterized this transfected variant of Tf-1 (Tf-1 beta) with regard to its response to lL-2. Unlike the parental Tf-1 cell line that is deficient in both lL- 2R alpha and lL-2R beta expression, the Tf-1 beta transfectant binds and responds to lL-2 through intermediate-affinity lL-2Rs. Scatchard analyses indicate the number of intermediate-affinity receptors on Tf-1 beta is similar to the number found on the well-characterized YT cell line. However, detection of gamma c on Tf-1 beta cells is dramatically less than on YT cells by Western blot analysis and is undetectable by flow cytometric studies and surface iodinations. The gamma c component on YT cells is readily detected by all three methods. We conclude from these studies that the intermediate-affinity lL-2Rs on the Tf-1 cell line behave differently than those on YT cells with respect to gamma c detection. Either the gamma c molecule itself is different, or the cellular environment in which it functions is altered. Elucidation of gamma c function on this cell line will allow for its use as a model in which other cytokines using gamma c (including lL-2, lL-4, and lL-15) can be studied on the same cellular background.

scholarly journals Pan-cancer analysis combined with experiments predicts CTHRC1 as a therapeutic target for human cancers

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Dazhao Peng ◽  
Cheng Wei ◽  
Xiaoyang Zhang ◽  
Shenghui Li ◽  
Hao Liang ◽  
...  
Keyword(s):  
Cell Lines ◽  
Therapeutic Target ◽  
Immune Cell ◽  
Single Gene ◽  
Wnt Signaling Pathway ◽  
Disease Process ◽  
Genetic Alterations ◽  
Human Cancers ◽  
And Function ◽  
Pan Cancer

Abstract Background The function of collagen triple helix repeat containing 1 (CTHRC1) as an oncogene has been reported in a growing number of publications. Bioinformatics methods represent a beneficial approach to examine the mechanism and function of the CTHRC1 gene in the disease process of cancers from a pan-cancer perspective. Methods In this study, using the online databases UCSC, NCBI, HPA, TIMER2, Oncomine, GEPIA, UALCAN, cBioPortal, COSMIC, MEXPRESS, STRING, CCLE, LinkedOmics, GTEx, TCGA, CGGA, and SangerBox, we focused on the relationship between CTHRC1 and tumorigenesis, progression, methylation, immunity, and prognosis. qPCR was used to detect CTHRC1 expression in glioma tissues and cell lines. Results The pan-cancer analysis showed that CTHRC1 was overexpressed in most tumors, and a significant correlation was observed between CTHRC1 expression and the prognosis of patients with cancer. CTHRC1 genetic alterations occur in diverse tumors and are associated with tumor progression. Levels of CTHRC1 promoter methylation were decreased in most cancer tissues compared with normal tissues. In addition, CTHRC1 coordinated the activity of ICP genes through diverse signal transduction pathways, was also associated with immune cell infiltration and the tumor microenvironment, and potentially represented a promising immunotherapy target. We identified CTHRC1-related genes across cancers using the GEPIA2 tool. The single-gene GO analysis of CTHRC1 across cancers showed that it was involved in some signaling pathways and biological processes, such as the Wnt signaling pathway, cell migration, and positive regulation of protein binding. The expression and function of CTHRC1 were also further verified in glioma tissues and cell lines. Conclusions CTHRC1 is overexpressed in various cancer types and functions as an important oncogene that may promote tumorigenesis and development through different mechanisms. CTHRC1 may represent an important therapeutic target for human cancers.

scholarly journals Review of: The rare ERBB2 variant Ile654Val is associated with an increased familial breast cancer risk

2005 ◽  
Vol 8 (12) ◽  
pp. 1-3
Author(s):  
I. G. Campbell
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Familial Breast Cancer ◽  
Transmembrane Domain ◽  
Genetic Alterations ◽  
Nucleotide Polymorphisms ◽  
Breast Cancers ◽  
Increased Risk ◽  
Familial Breast Cancer Risk

Citation of original article:B. Frank, K. Hemminki, M. Wirtenberger, J. L. Bermejo, P. Bugert, R. Klaes, R. K. Schmutzler, B. Wappenschmidt, C. R. Bartram, B. Burwinkel. The rare ERBB2 variant lle654Val is associated with an increased familial breast cancer risk. Carcinogenesis 2005; 26: 643–7.Abstract of the original articleOverexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20–30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer samples. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case–control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82–1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74–1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08–6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654–Val655 allele provokes receptor dimerisation and activation, thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.

scholarly journals Single-Cell Omics in Dissecting Immune Microenvironment of Malignant Gliomas—Challenges and Perspectives

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2264
Author(s):  
Bozena Kaminska ◽  
Natalia Ochocka ◽  
Pawel Segit
Keyword(s):  
Tumor Progression ◽  
Single Cell ◽  
Immune Cells ◽  
Rational Design ◽  
Malignant Gliomas ◽  
Genetic Alterations ◽  
Lymphoid Cells ◽  
Protein Targets ◽  
Cell Subpopulations ◽  
Definition Of

Single-cell technologies allow precise identification of tumor composition at the single‑cell level, providing high-resolution insights into the intratumoral heterogeneity and transcriptional activity of cells in the tumor microenvironment (TME) that previous approaches failed to capture. Malignant gliomas, the most common primary brain tumors in adults, are genetically heterogeneous and their TME consists of various stromal and immune cells playing an important role in tumor progression and responses to therapies. Previous gene expression or immunocytochemical studies of immune cells infiltrating TME of malignant gliomas failed to dissect their functional phenotypes. Single-cell RNA sequencing (scRNA-seq) and cytometry by time-of-flight (CyTOF) are powerful techniques allowing quantification of whole transcriptomes or >30 protein targets in individual cells. Both methods provide unprecedented resolution of TME. We summarize the findings from these studies and the current state of knowledge of a functional diversity of immune infiltrates in malignant gliomas with different genetic alterations. A precise definition of functional phenotypes of myeloid and lymphoid cells might be essential for designing effective immunotherapies. Single-cell omics studies have identified crucial cell subpopulations and signaling pathways that promote tumor progression, influence patient survival or make tumors vulnerable to immunotherapy. We anticipate that the widespread usage of single-cell omics would allow rational design of oncoimmunotherapeutics.

Late Onset of Secondary AML with 5q- in CLL with 13q- Abnormality; Coexistence of the Two Neoplastic Clones and the Therapeutic Potential of Lenalidomide.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4394-4394
Author(s):  
Imma Attolico ◽  
Giancarlo Discepoli ◽  
Roberta Nuccorini ◽  
Sara Pascale ◽  
Sabrina Coluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Peripheral Blood ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Disease Process ◽  
Lymphoid Cells ◽  
Fish Analysis ◽  
Prolymphocytic Leukemia ◽  
Increased Risk

Abstract Abstract 4394 Therapy-related acute myeloid leukemia (AML) and myelodysplastic syndrome (t-AML/MDS) are common after alkylating agents. t-AML/MDS related to alkylating agents are associated with monosomies or deletions of the long arm of chromosomes 5 and 7. Among patients with chronic lymphocytic leukemia (CLL), the potential for disease transformation to diffuse aggressive non-Hodgkin's lymphoma (Richter's syndrome) or the evolution to prolymphocytic leukemia is well known. However, the development of therapy related myelodysplastic syndrome (t-MDS) or t-AML is uncommon. In most trials, an incidence rate of 1% has been reported. We describe here a patient who developed t-AML twentyone years after treatment with chlorambucil and fludarabine for CLL, carrying a typical CLL-associated Chromosomal abnormality (CA), associated with a typical AML-related CA. In 1988 a 42-year-old man was found to have B-cell CLL (Binet stage B). Examination of the marrow showed infiltration by small lymphoid cells that expressed CD5, CD19, CD23, and weak surface immunoglobulin with lambda light chain restriction. The residual hematopoiesis was otherwise normal in morphology. During subsequent years he received courses of therapy with chlorambucil and fludarabine which resulted in partial remission. In June 2009 he developed pancytopenia (WBC 11.4×10e9/L, PMN 0.1×10e9/L, Hgb 7.7g/dL, PLT 26×10e9/L). Physical examination showed small, diffuse lymphadenopaties and splenomegaly. Peripheral blood film examination and immunophenotype were consistent with diagnosis of CLL. Bone marrow examination showed trilineage myelodisplasia with 25% blasts and 62% lymphocytes that expressed CD5, CD19, CD23 and sIg lambda, confirming the diagnosis of concurrent AML with multilineage dysplasia and CLL. Cytogenetic analysis showed a hyperdiploid karyotype with a number of chromosomes comprised between 47 and 55. FISH analysis of bone marrow showed del 5q in 50% of nuclei and biallelic deletion of 13q14 in 70% of nuclei. FISH analysis on peripheral blood confirmed deletion 13q14 in 80% of nuclei, and del 5q in 10% of nuclei; trisomy of 18 in 50% of nuclei was also present. Although patients with CLL have an increased risk for the development of second malignancies, solid tumors are most common. With regard to second hematologic malignancies, the risk of multiple myeloma in patients with CLL is increased 10-fold over the incidence of myeloma in the general population. However, AML develops in 1% or fewer of patients with CLL, despite the frequent and long-term use of alkylating agents for therapy, the older age of many of these patients, and their relatively long survival with this disease process. In a retrospective review by Robertson et al of 1,374 CLL patients who received care at the M.D. Anderson Cancer Center from 1972 to 1992, only three cases of MDS or AML were found. Seventy-two percent of these patients had received prior alkylator therapy. Anecdotal cases of myelodysplasia or AML occurring in untreated patients with CLL have been reported, as have cases of concomitant diagnoses of CLL and AML, although these are quite uncommon. These cases of secondary leukemia were generally refractory to therapy, with a median survival after diagnosis of approximately 1 month. Lenalidomide (Revlimid) is an immunomodulatory drug that yields a high frequency of erythroid, pathologic, and cytogenetic response in patients with myelodysplastic syndromes (MDS) with an interstitial deletion of the long arm of chromosome 5 (del 5q). Responses of AML with del 5q are also reported. Whether both the diseases will respond to this drug it is matter to prospectively investigate in these cases. Disclosures: No relevant conflicts of interest to declare.

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