Regulation of MHC class II expression in human T-cell malignancies

Abstract Expression of major histocompatibility complex (MHC) class II molecules in human activated T cells is under normal circumstances regulated exclusively by the CIITA-PIII subtype of the class II transactivator (CIITA). In this study, we show that the absence of MHC class II expression in leukemic T cells was due to a lack of expression of CIITA, whereas in T-lymphoma cells, expression of CIITA correlated with expression of MHC class II. Interestingly, activation of a CIITA-promoter (P)III–reporter construct was not affected in leukemic T cells. This revealed that the absence of endogenous CIITA expression was not caused by a lack of transcription factors critical for CIITA-PIII activation but suggests the involvement of an epigenetic silencing mechanism. Subsequent analysis showed that the lack of human leukocyte antigen–DR (HLA-DR) expression correlated with hypermethylation of CIITA-PIII in leukemic T-cell lines and in primary T-cell acute lymphoblastic leukemia (T-ALL) and a T-cell prolymphocytic leukemia (T-PLL). Treatment of leukemic T-cell lines with a demethylation agent showed re-expression of CIITA-PIII and HLA-DRA. Furthermore, in vitro methylation of CIITA-PIII and subsequent assessment of CIITA-PIII activity in Jurkat leukemic T cells resulted in reduction of constitutive and CREB-1 (cyclic adenosine monophosphate [cAMP]–response element binding protein 1)–induced promoter activity. Together, these results argue for an important role of DNA hyper-methylation in the control of CIITA expression in leukemic T cells.

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Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins

Blood ◽

10.1182/blood-2006-04-017863 ◽

2006 ◽

Vol 109 (8) ◽

pp. 3325-3332 ◽

Cited By ~ 38

Author(s):

Anders Woetmann ◽

Paola Lovato ◽

Karsten W. Eriksen ◽

Thorbjørn Krejsgaard ◽

Tord Labuda ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Mhc Class Ii ◽

Interleukin 2 ◽

Class Ii ◽

Bacterial Toxins ◽

Dependent Manner ◽

Malignant Cells ◽

T Cell Lines

AbstractBacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II–dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4+ T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.

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Reactivity of HTLV-transformed human T-cell lines to MHC class II antigens

Nature ◽

10.1038/312275a0 ◽

1984 ◽

Vol 312 (5991) ◽

pp. 275-277 ◽

Cited By ~ 28

Author(s):

Nicole Suciu-Foca ◽

Pablo Rubinstein ◽

Mikulas Popovic ◽

Robert C. Gallo ◽

Donald W. King

Keyword(s):

T Cell ◽

Cell Lines ◽

Mhc Class Ii ◽

Class Ii ◽

Human T Cell ◽

Mhc Class Ii Antigens ◽

T Cell Lines ◽

Class Ii Antigens

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Transforming Growth Factor β (TGF-β)-dependent Inhibition of T Helper Cell 2 (Th2)-induced Autoimmunity by Self–Major Histocompatibility Complex (MHC) Class II–specific, Regulatory CD4+ T Cell Lines

Journal of Experimental Medicine ◽

10.1084/jem.185.10.1769 ◽

1997 ◽

Vol 185 (10) ◽

pp. 1769-1775 ◽

Cited By ~ 124

Author(s):

Frank Bridoux ◽

Abdallah Badou ◽

Abdelhadi Saoudi ◽

Isabelle Bernard ◽

Elvira Druet ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Mhc Class Ii ◽

Class Ii ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Autoreactive T Cells ◽

T Cell Lines

Autoreactive anti–MHC class II T cells are found in Brown Norway (BN) and Lewis (LEW) rats that receive either HgCl2 or gold salts. These T cells have a T helper cell 2 (Th2) phenotype in the former strain and are responsible for Th2-mediated autoimmunity. In contrast, T cells that expand in LEW rats produce IL-2 and prevent experimental autoimmune encephalomyelitis, a cell-mediated autoimmune disease. The aim of this work was to investigate, using T cell lines derived from HgCl2-injected LEW rats (LEWHg), the effect of these autoreactive T cells on the development of Th2-mediated autoimmunity. The five LEWHg T cell lines obtained protect against Th2-mediated autoimmunity induced by HgCl2 in (LEW × BN)F1 hybrids. The lines produce, in addition to IL-2, IFN-γ and TGF-β, and the protective effect is TGF-β dependent since protection is abrogated by anti-TGF-β treatment. These results identify regulatory, TGF-β–producing, autoreactive T cells that are distinct from classical Th1 or Th2 and inhibit both Th1- and Th2-mediated autoimmune diseases.

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Activation of interleukin-13 expression in T cells from HTLV-1-infected individuals and in chronically infected cell lines

Blood ◽

10.1182/blood-2003-04-1043 ◽

2003 ◽

Vol 102 (12) ◽

pp. 4130-4136 ◽

Cited By ~ 27

Author(s):

Hye-Kyung Chung ◽

Howard A. Young ◽

Peter K. C. Goon ◽

Gisela Heidecker ◽

Gerald L. Princler ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Infected Cell ◽

Cell Lines ◽

Regulatory Protein ◽

Immunofluorescent Staining ◽

Cell Leukemia Virus Type ◽

Interleukin 13 ◽

Human T Cell ◽

T Cell Lines

Abstract Human T-cell leukemia virus type 1 (HTLV-1) infection profoundly alters T-cell gene expression, and the dysregulated synthesis of cytokines could influence the course and pathologic consequences of infection. In the process of screening T-cell lines for T helper 1 (Th1) and Th2 cytokine mRNAs, we observed that interleukin-13 (IL-13) mRNA was highly expressed in HTLV-1-infected, IL-2-dependent T-cell lines. IL-9 and interferon gamma (IFN-γ) mRNAs were also expressed at high levels in chronically infected cell lines. IL-5 mRNA was detected in 60% of the HTLV-1-infected cell lines, but mRNAs for IL-4, IL-10, IL-2, and IL-15 were either below detection limits or did not correlate with HTLV-1 infection. Transcriptional activation of the IL-13 promoter by the HTLV-1 Tax trans-regulatory protein was demonstrated in Jurkat T cells transiently transfected with an IL-13 promoter-reporter plasmid. The clinical relevance of these observations was demonstrated by immunofluorescent staining and flow cytometry of lymphocytes obtained from HTLV-1-infected patients. These studies revealed that IL-13 production was directly related to the level of Tax expression in the infected CD4+ T cells soon after in vitro culture. As IL-13 plays key roles in tumor immunosurveillance, asthma, and central nervous system inflammation, it may contribute to the pathophysiology of HTLV-1-associated diseases. (Blood. 2003;102:4130-4136)

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Adoptive T-Cell Therapy for B-Cell Acute Lymphoblastic Leukemia: Preclinical Studies

Blood ◽

10.1182/blood.v94.10.3531.422k14_3531_3540 ◽

1999 ◽

Vol 94 (10) ◽

pp. 3531-3540 ◽

Cited By ~ 22

Author(s):

Angelo A. Cardoso ◽

J. Pedro Veiga ◽

Paolo Ghia ◽

Hernani M. Afonso ◽

W. Nicholas Haining ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

B Cell ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Adoptive T Cell Therapy ◽

Leukemic Cells ◽

Acute Leukemias ◽

T Cell Lines

We have previously shown that leukemia-specific cytotoxic T cells (CTL) can be generated from the bone marrow of most patients with B-cell precursor acute leukemias. If these antileukemia CTL are to be used for adoptive immunotherapy, they must have the capability to circulate, migrate through endothelium, home to the bone marrow, and, most importantly, lyse the leukemic cells in a leukemia-permissive bone marrow microenvironment. We demonstrate here that such antileukemia T-cell lines are overwhelmingly CD8+ and exhibit an activated phenotype. Using a transendothelial chemotaxis assay with human endothelial cells, we observed that these T cells can be recruited and transmigrate through vascular and bone marrow endothelium and that these transmigrated cells preserve their capacity to lyse leukemic cells. Additionally, these antileukemia T-cell lines are capable of adhering to autologous stromal cell layers. Finally, autologous antileukemia CTL specifically lyse leukemic cells even in the presence of autologous marrow stroma. Importantly, these antileukemia T-cell lines do not lyse autologous stromal cells. Thus, the capacity to generate anti–leukemia-specific T-cell lines coupled with the present findings that such cells can migrate, adhere, and function in the presence of the marrow microenvironment enable the development of clinical studies of adoptive transfer of antileukemia CTL for the treatment of ALL.

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Reactivation of a major histocompatibility complex class II gene in mouse plasmacytoma cells and mouse T cells.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1465 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1465-1469 ◽

Cited By ~ 13

Author(s):

C H Chang ◽

W L Fodor ◽

R A Flavell

Keyword(s):

Gene Expression ◽

T Cells ◽

T Cell ◽

B Cells ◽

Mhc Class Ii ◽

Class Ii ◽

Histocompatibility Complex ◽

Human T Cell ◽

Human T Cell Line ◽

Mhc Class Ii Genes

Terminally differentiated plasma cells and mouse T cells do not express major histocompatibility complex (MHC) class II genes although class II gene expression is observed in pre-B and mature B cells as well as in activated human T cells. Transient heterokaryons were prepared and analyzed to investigate the mechanisms of inactivation of MHC class II gene in mouse plasmacytoma cells and mouse T cells. The endogenous MHC class II genes in both mouse plasmacytoma cells and mouse T cells can be reactivated by factors present in B cells. This reactivation of class II gene is also observed by fusion with a human T cell line which expresses MHC class II genes, but not with a class II negative human T cell line. It appears that the loss of MHC class II gene expression during the terminal differentiation of B cells or T cell lineage is due to absence of positive regulatory factor(s) necessary for class II transcription.

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Generation of Cytomegalovirus-Specific T Lymphocytes Using Protein-Spanning Pools of pp65-Derived Over-Lapping Pentadecapeptides for Adoptive Immunotherapy.

Blood ◽

10.1182/blood.v104.11.2236.2236 ◽

2004 ◽

Vol 104 (11) ◽

pp. 2236-2236

Author(s):

Guenther Koehne ◽

Deepa Trivedi ◽

Roxanne Y. Williams ◽

Richard J. O’Reilly

Keyword(s):

T Cells ◽

T Cell ◽

Cell Lines ◽

Cd8 T Cells ◽

Adoptive Immunotherapy ◽

Hla Class I ◽

Class Ii ◽

Hla Alleles ◽

Hla Genotypes ◽

T Cell Lines

Abstract Cell-mediated immunity is essential for control of human cytomegalovirus (HCMV) infection. We utilized a pool of 138 synthetic overlapping pentadecapeptides over-spanning the entire pp65 protein to generate polyclonal CMV-specific T-cell lines from 12 CMV-seropositive donors inheriting different HLA genotypes. Autologous monocyte-derived dendritic cells (DCs) pulsed with this complete pool consistently induced highly specific T-cells and in analyses of T-cell lines from 5 separate HLA-A*0201+ individuals demonstrate that this pp65-derived pentadecapeptide-pool selectively induced T-cells specifically reactive against sub-pools of pentadecapeptides which contained the HLA-A*0201 binding epitope NLVPMVATV. The specificity of these T-cells for this immunodominant nonapeptide was confirmed by MHC-tetramer staining and intracellular interferon-γ production, demonstrating that 38 – 60% of the CD8+ cell population were specific for this A*2-restricted peptide after 3 weeks of culture. These T cells also killed both nonapeptide-pulsed and CMV-infected target cells. In subsequent experiments using auotlogous monocyte-derived DC’s pulsed with the pentadecapeptide pool for the stimulation of CMV-specific T-cell lines in individuals other than HLA-A*2, the generated T cells selectively recognized 1–3 pentadecapeptides identified by secondary responses to a mapping grid of pentadecapeptide subpools with single overlaps. Responses against peptide loaded targets sharing single HLA class I or II alleles permitted the identification the restricting HLA alleles. Those T-cell lines from HLA-A*2 neg. donors contained high frequencies of CD4 and/or CD8 T-cells selectively reactive against peptides presented by other HLA alleles including known epitopes such as aa 341–350QYDPVAALF (HLA-A*2402) as well as unreported epitopes such as aa 267–275HERNGFTVL (HLA-B*4001 and B* 4002). In some donors, the peptide-specific IFN-g+ T-cells generated have been predominantly CD4+ T-cells. Like the peptide-specific CD8+ T-cells, we could determine both epitope and HLA-class II restricting element, e.g. aa513–523 FFWDANDIYRI (HLA-DRB1* 1301). These CD4+ T-cells also consistently exhibited cytotoxic activity against infected targets as well as peptide-loaded cells expressing the restricting HLA class II allele. Thus, synthetic overlapping pentadecapeptides spanning the sequence of the immunodominant protein of CMV-pp65, when loaded on DCs can consistently stimulate the in vitro generation of CD8+ and CD4+ T-cell lines from seropositive donors of diverse HLA genotypes. These cell lines are selectively enriched for T-cells specific for a limited number of immunodominant epitopes each presented by a single HLA class I or class II allele. This approach fosters expansion and selection of HLA-restricted CMV-pp65-reactive T-cell lines of high specificity which also lyse CMV-infected targets and may have advantages for generating virus-specific T-cells for adoptive immunotherapy.

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IMMUNOBIOLOGICAL CHARACTERISTICS OF THE SLA P1-SPECIFIC HUMAN T CELL LINES AND THE P1 EPITOPE ANALYSIS IN CONTEXT OF HLA CLASS II MOLECULES

Transplantation Journal ◽

10.1097/00007890-200407271-01582 ◽

2004 ◽

Vol 78 ◽

pp. 587-588

Author(s):

J Tang ◽

Y Zhou ◽

J Xie ◽

K -Y. Chou

Keyword(s):

T Cell ◽

Cell Lines ◽

Class Ii ◽

Hla Class Ii ◽

Epitope Analysis ◽

Human T Cell ◽

T Cell Lines ◽

Hla Class Ii Molecules

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Activation of hypoxia-inducible factor 1 in human T-cell leukaemia virus type 1-infected cell lines and primary adult T-cell leukaemia cells

Biochemical Journal ◽

10.1042/bj20070286 ◽

2007 ◽

Vol 406 (2) ◽

pp. 317-323 ◽

Cited By ~ 31

Author(s):

Mariko Tomita ◽

Gregg L. Semenza ◽

Canine Michiels ◽

Takehiro Matsuda ◽

Jun-Nosuke Uchihara ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Protein Expression ◽

Cell Lines ◽

Transcriptional Activity ◽

Cell Leukaemia ◽

Leukaemia Virus ◽

Human T Cell ◽

T Cell Lines

HTLV-1 (human T-cell leukaemia virus type 1) is the causative agent for ATL (adult T-cell leukaemia). HTLV-1 Tax can activate the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway, which is responsible for survival of HTLV-1-infected T-cells. HIFs (hypoxia-inducible factors) are transcriptional regulators that play a central role in the response to hypoxia. Overexpression of HIF-1α in many cancers is associated with a poor response to treatment and increased patient mortality. Our objectives in the present study were to investigate whether HIF-1 was activated in HTLV-1-infected T-cells and to elucidate the molecular mechanisms of HIF-1 activation by focusing on the PI3K/Akt signalling pathway. We detected a potent pathway that activated HIF-1 in the HTLV-1-infected T-cells under a normal oxygen concentration. Enhanced HIF-1α protein expression and HIF-1 DNA-binding activity were exhibited in HTLV-1-infected T-cell lines. Knockdown of HIF-1α by siRNA (small interfering RNA) suppressed the growth and VEGF (vascular endothelial growth factor) expression of the HTLV-1-infected T-cell line. HIF-1 protein accumulation and transcriptional activity were enhanced by Tax, which was inhibited by dominant-negative Akt. Importantly, mutant forms of Tax that are defective in activation of the PI3K/Akt pathway failed to induce HIF-1 transcriptional activity. The PI3K inhibitor LY294002 suppressed HIF-1α protein expression, HIF-1 DNA-binding and HIF-1 transcriptional activity in HTLV-1-infected T-cell lines. In primary ATL cells, HIF-1α protein levels were strongly correlated with levels of phosphorylated Akt. The results of the present study suggest that PI3K/Akt activation induced by Tax leads to activation of HIF-1. As HIF-1 plays a major role in tumour progression, it may represent a molecular target for the development of novel ATL therapeutics.

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