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T Cells Expressing Checkpoint Receptor TIGIT Are Enriched in Follicular Lymphoma Tumors and Characterized by Reversible Suppression of T-cell Receptor Signaling.
Josefsson SE, Huse K, Kolstad A, Beiske K, Pende D, Steen CB, Inderberg EM, Lingjærde OC, Østenstad B, Smeland EB, Levy R, Irish JM, Myklebust JH
(2018) Clin Cancer Res 24: 870-881
MeSH Terms: Antigens, Differentiation, T-Lymphocyte, CD8-Positive T-Lymphocytes, Cytokines, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, Follicular, Receptors, Antigen, T-Cell, Receptors, Immunologic, Signal Transduction, T-Lymphocyte Subsets, Tumor Microenvironment
Show Abstract · Added December 15, 2017
T cells infiltrating follicular lymphoma (FL) tumors are considered dysfunctional, yet the optimal target for immune checkpoint blockade is unknown. Characterizing coinhibitory receptor expression patterns and signaling responses in FL T-cell subsets might reveal new therapeutic targets. Surface expression of 9 coinhibitory receptors governing T-cell function was characterized in T-cell subsets from FL lymph node tumors and from healthy donor tonsils and peripheral blood samples, using high-dimensional flow cytometry. The results were integrated with T-cell receptor (TCR)-induced signaling and cytokine production. Expression of T-cell immunoglobulin and ITIM domain (TIGIT) ligands was detected by immunohistochemistry. TIGIT was a frequently expressed coinhibitory receptor in FL, expressed by the majority of CD8 T effector memory cells, which commonly coexpressed exhaustion markers such as PD-1 and CD244. CD8 FL T cells demonstrated highly reduced TCR-induced phosphorylation (p) of ERK and reduced production of IFNγ, while TCR proximal signaling (p-CD3ζ, p-SLP76) was not affected. The TIGIT ligands CD112 and CD155 were expressed by follicular dendritic cells in the tumor microenvironment. Dysfunctional TCR signaling correlated with TIGIT expression in FL CD8 T cells and could be fully restored upon culture. The costimulatory receptor CD226 was downregulated in TIGIT compared with TIGIT CD8 FL T cells, further skewing the balance toward immunosuppression. TIGIT blockade is a relevant strategy for improved immunotherapy in FL. A deeper understanding of the interplay between coinhibitory receptors and key T-cell signaling events can further assist in engineering immunotherapeutic regimens to improve clinical outcomes of cancer patients. .
©2017 American Association for Cancer Research.
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12 MeSH Terms
Adipose Tissue is Enriched for Activated and Late-Differentiated CD8+ T Cells and Shows Distinct CD8+ Receptor Usage, Compared With Blood in HIV-Infected Persons.
Koethe JR, McDonnell W, Kennedy A, Abana CO, Pilkinton M, Setliff I, Georgiev I, Barnett L, Hager CC, Smith R, Kalams SA, Hasty A, Mallal S
(2018) J Acquir Immune Defic Syndr 77: e14-e21
MeSH Terms: Adipose Tissue, Adult, Anti-HIV Agents, Blood Cells, CD8-Positive T-Lymphocytes, Cohort Studies, Female, HIV Infections, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, Sequence Analysis, DNA, Sustained Virologic Response, T-Lymphocyte Subsets
Show Abstract · Added March 14, 2018
BACKGROUND - Adverse viral and medication effects on adipose tissue contribute to the development of metabolic disease in HIV-infected persons, but T cells also have a central role modulating local inflammation and adipocyte function. We sought to characterize potentially proinflammatory T-cell populations in adipose tissue among persons on long-term antiretroviral therapy and assess whether adipose tissue CD8 T cells represent an expanded, oligoclonal population.
METHODS - We recruited 10 HIV-infected, non-diabetic, overweight or obese adults on efavirenz, tenofovir, and emtricitabine for >4 years with consistent viral suppression. We collected fasting blood and subcutaneous abdominal adipose tissue to measure the percentage of CD4 and CD8 T cells expressing activation, exhaustion, late differentiation/senescence, and memory surface markers. We performed T-cell receptor (TCR) sequencing on sorted CD8 cells. We compared the proportion of each T-cell subset and the TCR repertoire diversity, in blood versus adipose tissue.
RESULTS - Adipose tissue had a higher percentage of CD3CD8 T cells compared with blood (61.0% vs. 51.7%, P < 0.01) and was enriched for both activated CD8HLA-DR T cells (5.5% vs. 0.9%, P < 0.01) and late-differentiated CD8CD57 T cells (37.4% vs. 22.7%, P < 0.01). Adipose tissue CD8 T cells displayed distinct TCRβ V and J gene usage, and the Shannon Entropy index, a measure of overall TCRβ repertoire diversity, was lower compared with blood (4.39 vs. 4.46; P = 0.05).
CONCLUSIONS - Adipose tissue is enriched for activated and late-differentiated CD8 T cells with distinct TCR usage. These cells may contribute to tissue inflammation and impaired adipocyte fitness in HIV-infected persons.
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15 MeSH Terms
Agonist immunotherapy restores T cell function following MEK inhibition improving efficacy in breast cancer.
Dushyanthen S, Teo ZL, Caramia F, Savas P, Mintoff CP, Virassamy B, Henderson MA, Luen SJ, Mansour M, Kershaw MH, Trapani JA, Neeson PJ, Salgado R, McArthur GA, Balko JM, Beavis PA, Darcy PK, Loi S
(2017) Nat Commun 8: 606
MeSH Terms: 4-1BB Ligand, Animals, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Female, Humans, Immunotherapy, Lymphocytes, Tumor-Infiltrating, MAP Kinase Kinase 1, MAP Kinase Kinase 2, MAP Kinase Signaling System, Mammary Neoplasms, Animal, Mice, OX40 Ligand, Protein Kinase Inhibitors, Pyridones, Pyrimidinones, T-Lymphocyte Subsets, T-Lymphocytes, Triple Negative Breast Neoplasms
Show Abstract · Added March 14, 2018
The presence of tumor-infiltrating lymphocytes in triple-negative breast cancers is correlated with improved outcomes. Ras/MAPK pathway activation is associated with significantly lower levels of tumor-infiltrating lymphocytes in triple-negative breast cancers and while MEK inhibition can promote recruitment of tumor-infiltrating lymphocytes to the tumor, here we show that MEK inhibition adversely affects early onset T-cell effector function. We show that α-4-1BB and α-OX-40 T-cell agonist antibodies can rescue the adverse effects of MEK inhibition on T cells in both mouse and human T cells, which results in augmented anti-tumor effects in vivo. This effect is dependent upon increased downstream p38/JNK pathway activation. Taken together, our data suggest that although Ras/MAPK pathway inhibition can increase tumor immunogenicity, the negative impact on T-cell activity is functionally important. This undesirable impact is effectively prevented by combination with T-cell immune agonist immunotherapies resulting in superior therapeutic efficacy.MEK inhibition in breast cancer is associated with increased tumour infiltrating lymphocytes (TILs), however, MAPK activity is required for T cells function. Here the authors show that TILs activity following MEK inhibition can be enhanced by agonist immunotherapy resulting in synergic therapeutic effects.
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21 MeSH Terms
Intracellular Staining and Flow Cytometry to Identify Lymphocyte Subsets within Murine Aorta, Kidney and Lymph Nodes in a Model of Hypertension.
Laroumanie F, Dale BL, Saleh MA, Madhur MS
(2017) J Vis Exp :
MeSH Terms: Angiotensin II, Animals, Aorta, Cytokines, Disease Models, Animal, Flow Cytometry, Hypertension, Kidney, Lymph Nodes, Mice, Staining and Labeling, T-Lymphocyte Subsets
Show Abstract · Added September 7, 2017
It is now well known that T lymphocytes play a critical role in the development of several cardiovascular diseases. For example, studies from our group have shown that hypertension is associated with an excessive accumulation of T cells in the vessels and kidney during the development of experimental hypertension. Once in these tissues, T cells produce several cytokines that affect both vascular and renal function leading to vasoconstriction and sodium and water retention. To fully understand how T cells cause cardiovascular and renal diseases, it is important to be able to identify and quantify the specific T cell subsets present in these tissues. T cell subsets are defined by a combination of surface markers, the cytokines they secrete, and the transcription factors they express. The complexity of the T cell population makes flow cytometry and intracellular staining an invaluable technique to dissect the phenotypes of the lymphocytes present in tissues. Here, we provide a detailed protocol to identify the surface and intracellular markers (cytokines and transcription factors) in T cells isolated from murine kidney, aorta and aortic draining lymph nodes in a model of angiotensin II induced hypertension. The following steps are described in detail: isolation of the tissues, generation of the single cell suspensions, ex vivo stimulation, fixation, permeabilization and staining. In addition, several fundamental principles of flow cytometric analyses including choosing the proper controls and appropriate gating strategies are discussed.
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12 MeSH Terms
Mass Cytometry of Follicular Lymphoma Tumors Reveals Intrinsic Heterogeneity in Proteins Including HLA-DR and a Deficit in Nonmalignant Plasmablast and Germinal Center B-Cell Populations.
Wogsland CE, Greenplate AR, Kolstad A, Myklebust JH, Irish JM, Huse K
(2017) Cytometry B Clin Cytom 92: 79-87
MeSH Terms: B-Lymphocytes, Flow Cytometry, Germinal Center, HLA-DR Antigens, Humans, Immunophenotyping, Lymphoma, B-Cell, Lymphoma, Follicular, Plasma Cells, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2016
BACKGROUND - Follicular lymphoma (FL) is an indolent non-Hodgkin lymphoma that has a risk of transformation to more aggressive lymphoma. Relatively little is known about the nonmalignant B-cell and T-cell subset composition within the tumor microenvironment and whether altered phenotypes are associated with patterns of lymphoma B-cell heterogeneity.
METHODS - Two mass cytometry (CyTOF) panels were designed to immunophenotype B and T cells in FL tumors. Populations of malignant B cells, nonmalignant B cells, and T cells from each FL tumor were identified and their phenotypes compared to B and T cells from healthy human tonsillar tissue.
RESULTS - Diversity in cellular phenotype between tumors was greater for the malignant B cells than for nonmalignant B or T cells. The malignant B-cell population bore little phenotypic similarity to any healthy B-cell subset, and unexpectedly clustered closer to naïve B-cell populations than GC B-cell populations. Among the nonmalignant B cells within FL tumors, a significant lack of GC and plasmablast B cells was observed relative to tonsil controls. In contrast, nonmalignant T cells in FL tumors were present at levels similar to their cognate tonsillar T-cell subsets.
CONCLUSION - Mass cytometry revealed that diverse HLA-DR expression on FL cells within individual tumors contributed greatly to tumor heterogeneity. Both malignant and nonmalignant B cells in the tumor bore little phenotypic resemblance to healthy GC B cells despite the presence of T follicular helper cells in the tumor. These findings suggest that ongoing signaling interactions between malignant B cells and intra-tumor T cells shape the tumor microenvironment. © 2016 International Clinical Cytometry Society.
© 2016 International Clinical Cytometry Society.
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10 MeSH Terms
Histone Deacetylase 3 Is Required for T Cell Maturation.
Hsu FC, Belmonte PJ, Constans MM, Chen MW, McWilliams DC, Hiebert SW, Shapiro VS
(2015) J Immunol 195: 1578-90
MeSH Terms: Animals, Bone Marrow Cells, Cell Differentiation, Cell Movement, Complement Activation, Complement System Proteins, Histone Deacetylases, Homeostasis, Interleukin-7, Lymphocyte Count, Mice, Mice, Knockout, Mice, Transgenic, T-Lymphocyte Subsets, T-Lymphocytes, Thymus Gland, Tumor Necrosis Factors
Show Abstract · Added September 28, 2015
Recent thymic emigrants are newly generated T cells that need to undergo postthymic maturation to gain functional competency and enter the long-lived naive T cell pool. The mechanism of T cell maturation remains incompletely understood. Previously, we demonstrated that the transcriptional repressor NKAP is required for T cell maturation. Because NKAP associates with histone deacetylase 3 (HDAC3), we examined whether HDAC3 is also required for T cell maturation. Although thymic populations are similar in CD4-cre HDAC3 conditional knockout mice compared with wild-type mice, the peripheral numbers of CD4(+) and CD8(+) T cells are dramatically decreased. In the periphery, the majority of HDAC3-deficient naive T cells are recent thymic emigrants, indicating a block in T cell maturation. CD55 upregulation during T cell maturation is substantially decreased in HDAC3-deficient T cells. Consistent with a block in functional maturation, HDAC3-deficient peripheral T cells have a defect in TNF licensing after TCR/CD28 stimulation. CD4-cre HDAC3 conditional knockout mice do not have a defect in intrathymic migration, thymic egress, T cell survival, or homeostasis. In the periphery, similar to immature NKAP-deficient peripheral T cells, HDAC3-deficient peripheral T cells were bound by IgM and complement proteins, leading to the elimination of these cells. In addition, HDAC3-deficient T cells display decreases in the sialic acid modifications on the cell surface that recruit natural IgM to initiate the classical complement pathway. Therefore, HDAC3 is required for T cell maturation.
Copyright © 2015 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Innate and virtual memory T cells in man.
Van Kaer L
(2015) Eur J Immunol 45: 1916-20
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Humans, Immunity, Innate, Immunologic Memory, Mice, T-Lymphocyte Subsets
Show Abstract · Added September 28, 2015
A hallmark of the antigen-specific B and T lymphocytes of the adaptive immune system is their capacity to "remember" pathogens long after they are first encountered, a property that forms the basis for effective vaccine development. However, studies in mice have provided strong evidence that some naive T cells can develop characteristics of memory T cells in the absence of foreign antigen encounters. Such innate memory T cells may develop in response to lymphopenia or the presence of high levels of the cytokine IL-4, and have also been identified in unmanipulated animals, a phenomenal referred to as "virtual memory." While the presence of innate memory T cells in mice is now widely accepted, their presence in humans has not yet been fully validated. In this issue of the European Journal of Immunology, Jacomet et al. [Eur. J. Immunol. 2015. 45:1926-1933] provide the best evidence to date for innate memory T cells in humans. These findings may contribute significantly to our understanding of human immunity to microbial pathogens and tumors.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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7 MeSH Terms
Inflammation, immunity, and hypertensive end-organ damage.
McMaster WG, Kirabo A, Madhur MS, Harrison DG
(2015) Circ Res 116: 1022-33
MeSH Terms: Adaptive Immunity, Animals, Benzylamines, Cardiovascular Diseases, Cytokines, Drug Evaluation, Preclinical, Humans, Hypertension, Immunity, Innate, Inflammation, Kidney, Lymphocyte Activation, Mice, Mice, Knockout, Models, Animal, Models, Cardiovascular, Models, Immunological, Oxidative Stress, Reactive Oxygen Species, Signal Transduction, T-Lymphocyte Subsets, Vascular Remodeling, Vascular Stiffness
Show Abstract · Added March 31, 2015
For >50 years, it has been recognized that immunity contributes to hypertension. Recent data have defined an important role of T cells and various T cell-derived cytokines in several models of experimental hypertension. These studies have shown that stimuli like angiotensin II, deoxycorticosterone acetate-salt, and excessive catecholamines lead to formation of effector like T cells that infiltrate the kidney and perivascular regions of both large arteries and arterioles. There is also accumulation of monocyte/macrophages in these regions. Cytokines released from these cells, including interleukin-17, interferon-γ, tumor necrosis factorα, and interleukin-6 promote both renal and vascular dysfunction and damage, leading to enhanced sodium retention and increased systemic vascular resistance. The renal effects of these cytokines remain to be fully defined, but include enhanced formation of angiotensinogen, increased sodium reabsorption, and increased renal fibrosis. Recent experiments have defined a link between oxidative stress and immune activation in hypertension. These have shown that hypertension is associated with formation of reactive oxygen species in dendritic cells that lead to formation of gamma ketoaldehydes, or isoketals. These rapidly adduct to protein lysines and are presented by dendritic cells as neoantigens that activate T cells and promote hypertension. Thus, cells of both the innate and adaptive immune system contribute to end-organ damage and dysfunction in hypertension. Therapeutic interventions to reduce activation of these cells may prove beneficial in reducing end-organ damage and preventing consequences of hypertension, including myocardial infarction, heart failure, renal failure, and stroke.
© 2015 American Heart Association, Inc.
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23 MeSH Terms
Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.
Weitkamp JH, Rosen MJ, Zhao Z, Koyama T, Geem D, Denning TL, Rock MT, Moore DJ, Halpern MD, Matta P, Denning PW
(2014) PLoS One 9: e99042
MeSH Terms: Animals, Cells, Cultured, Enterocolitis, Necrotizing, Female, Gene Expression Regulation, Humans, Infant, Newborn, Infant, Premature, Interleukin-17, Intestine, Small, Male, Mice, Mice, Inbred C57BL, Occludin, Receptors, Antigen, T-Cell, gamma-delta, T-Lymphocyte Subsets
Show Abstract · Added June 10, 2014
BACKGROUND - Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17.
OBJECTIVE - We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls.
RESULTS - In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A.
CONCLUSION - Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.
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16 MeSH Terms
Dysregulated CD4+ T cells from SLE-susceptible mice are sufficient to accelerate atherosclerosis in LDLr-/- mice.
Wilhelm AJ, Rhoads JP, Wade NS, Major AS
(2015) Ann Rheum Dis 74: 778-85
MeSH Terms: Animals, Atherosclerosis, CD4-Positive T-Lymphocytes, Disease Models, Animal, Forkhead Transcription Factors, Lupus Erythematosus, Systemic, Mice, Mice, Inbred Strains, Mice, Knockout, Receptors, Interleukin-10, Receptors, LDL, T-Lymphocyte Subsets, T-Lymphocytes, Regulatory
Show Abstract · Added February 11, 2014
OBJECTIVE - Accelerated atherosclerosis is a major source of morbidity in systemic lupus erythematosus (SLE). However, the cause of SLE-accelerated atherosclerosis remains unclear.
METHODS - CD4(+) T cells from C57/Bl/6 (B6) or SLE-susceptible B6.Sle1.2.3 (B6.SLE) mice were transferred into LDLr(-/-), Rag(-/-) mice. T cells were examined for cytokine production and expression of interleukin-10 receptor (IL-10R) and functional markers. T cells were isolated based on FoxP3(GFP) expression and transferred to LDLr(-/-), Rag(-/-) mice to establish a role for B6.SLE effector T cells (Teff) in atherosclerosis.
RESULTS - Mice receiving whole B6.SLE CD4(+) T cells displayed no other SLE phenotype; however, atherosclerosis was increased nearly 40%. We noted dysregulated IL-17 production and reduced frequency of IL-10R expression by B6.SLE regulatory T cells (Treg). Functional assays indicated resistance of B6.SLE Teff to suppression by both B6.SLE and B6 Treg. Transfer experiments with CD4(+)FoxP3(-) Teff and CD4(+)FoxP3(+) Treg from B6.SLE and B6 mice, respectively, resulted in increased atherosclerosis compared with B6 Teff and Treg recipients. Treg isolated from mice receiving B6.SLE Teff with B6 Treg had increased production of IL-17 and fewer expressed IL-10R compared with B6 Teff and Treg transfer.
CONCLUSIONS - Transfer of B6.SLE Teff to LDLr(-/-), Rag(-/-) mice results in accelerated atherosclerosis independent of the source of Treg. In addition, the presence of B6.SLE Teff resulted in more IL-17-producing Treg and fewer expressing IL-10R, suggesting that B6.SLE Teff may mediate phenotypic changes in Treg. To our knowledge, this is the first study to provide direct evidence of the role of B6.SLE Teff in accelerating atherosclerosis through resistance to Treg suppression.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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13 MeSH Terms