Expression of Lymphocyte Activation Gene 3 (LAG-3/CD223) by Chronic Lymphocytic Leukemia B Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2952-2952
Author(s):  
Han-Yu Chuang ◽  
Yu-Tsueng Liu ◽  
Laura Z. Rassenti ◽  
Lang Huynh ◽  
Dennis Carson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Lymphocytic Leukemia ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

Abstract The clinical course of chronic lymphocytic leukemia (CLL) is variable. DNA-microarray studies have shown that the gene-expression patterns of CLL cells with unmutated IgVH genes are similar to those of cells with mutated IgVH genes, but that the patterns of both are distinct from those of other leukemias and lymphomas. Nevertheless, the two subtypes of CLL can be distinguished by the differential expression of a small number of genes, one of which encodes ZAP-70, an intracellular tyrosine kinase with a critical role in T-cell receptor signaling. Further analysis of the mutation status of IgVH genes and ZAP-70 expression revealed that CLL patients with B cells expressing ZAP-70 and unmutated IgVH genes had a more aggressive disease. LAG-3 (CD223) is thought to play a role in immune responses mediated by T and NK cells. LAG-3, a CD4 homolog, is a ligand for MHC class II antigens. Similar to ZAP-70, LAG-3 is selectively expressed on activated T and NK cells and has recently been shown to be expressed on T-cell activated B cells. We compared the gene expression profiles of the B cells purified from 15 CLL patients using the Affymetrix HG-U133 plus 2.0. This analysis revealed LAG-3 and parathymosin differentially expressed at higher levels by the CLL cells expressing ZAP-70 and unmutated IgVH genes. LAG-3 and parathymosin are located on chromosome 12p13 with head-to-tail orientation. To examine for surface expression of LAG-3, we performed flow cytometry on these same 15 CLL samples using an anti LAG-3 mAb (CD223). We found LAG-3 expressed at high levels by the CD5/CD19 B cells of 4/8 (50%) cases that expressed ZAP-70 and unmutated IgVH genes. Conversely, the samples with B cells lacking ZAP-70 and with mutated IgVH genes did not express LAG-3 (0/7). All samples (15/15) expressed high level of MHC class II antigens, as assessed by flow cytometry. LAG-3 may interact with MHC class II molecules expressed by CLL cells to form an autocrine loop that may further enhance the activation of ZAP-70-expressing CLL B cells. Further analysis is needed to delineate the role of LAG-3 in the pathogenesis and/or progression of this disease.

scholarly journals Induction of human IgE synthesis requires interleukin 4 and T/B cell interactions involving the T cell receptor/CD3 complex and MHC class II antigens.

1989 ◽  
Vol 169 (4) ◽  
pp. 1295-1307 ◽  
Author(s):  
D Vercelli ◽  
H H Jabara ◽  
K Arai ◽  
R S Geha
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Class Ii ◽  
Ige Synthesis ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

The induction of IgE synthesis by IL-4 requires T cells and monocytes, as well as T cell- and monocyte-derived cytokines. Optimal cytokine combinations, however, fail to induce highly purified B cells to secrete IgE, indicating that additional signals are required. We show herein that the induction of human IgE synthesis by rIL-4 requires cognate interaction between the T cell receptor/CD3 complex on T cells and MHC class II antigens on B cells: mAbs directed against these molecules completely blocked IL-4-dependent IgE induction. mAbs against cell adhesion molecules (CD2, CD4, LFA-1) also inhibited IgE synthesis induced by IL-4, confirming that cell-cell contact is necessary for IgE induction. The requirement for cognate T/B cell interaction was further shown by comparing the IgE-inducing ability of two human IL-4-producing alloreactive T cell clones: F6, which recognizes MHC class II antigens on both B cells and monocytes, and A1, which recognizes an HLA-DP-associated epitope expressed on monocytes, but not on B cells. When incubated with B cells and monocytes from a normal donor bearing the appropriate alloantigen, clone F6, but not clone A1, induced vigorous IgE synthesis, although both clones proliferated and secreted IL-4. Taken together, our results suggest that at least two, possibly synergizing, signals are required for the T cell-dependent induction of IgE synthesis by B cells: one signal is delivered by cognate T/B cell interaction, the other by T cell-derived IL-4.

The role of N-linked oligosaccharides of MHC class II antigens in T cell stimulation

1994 ◽  
Vol 172 (1) ◽  
pp. 95-104 ◽  
Author(s):  
Bishwajit Nag ◽  
H. Garrett Wada ◽  
Subhashini Arimilli ◽  
Katherine Fok ◽  
David Passmore ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Cell Stimulation ◽  
T Cell Stimulation ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

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

1992 ◽  
Vol 176 (5) ◽  
pp. 1465-1469 ◽  
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.

scholarly journals Two levels of help for B cell alloantibody production.

1996 ◽  
Vol 183 (2) ◽  
pp. 699-703 ◽  
Author(s):  
D J Steele ◽  
T M Laufer ◽  
S T Smiley ◽  
Y Ando ◽  
M J Grusby ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Igg Antibodies ◽  
Cd4 Cells ◽  
Mhc Class Ii Antigens ◽  
Cd4 Cell ◽  
Class Ii Antigens ◽  
Deficient Mice

We have examined whether T cell stimulation by direct or indirect pathways contributes to alloantibody production by B cells after major histocompatibility complex (MHC)-disparate skin graft rejection in mice. Experiments were performed using normal mice, MHC class II-deficient mice, MHC class II-deficient mice with an intact peripheral CD4+ cell population (due to expression of class II antigens only on thymic epithelium), mice lacking the cytoplasmic tail of their MHC class II antigens, and mice depleted of CD4+ cells by anti-CD4 monoclonal antibody treatment. Depletion of recipient CD4+ cells reduced alloantibody production to barely detectable levels. Absence of donor MHC class II antigens did not affect the production of either immunoglobulin (Ig)M or IgG antibodies directed at class I alloantigens. Absence of recipient MHC class II antigens, however, led to production of only IgM but not IgG antibodies, even if the recipients had an intact CD4+ cell population. Absence of the cytoplasmic tail of the recipient's MHC class II antigens led to the production of slightly reduced amounts of IgG antibody. These findings indicate that (a) CD4+ cells are essential helper cells for B cell alloantibody production; (b) production of IgM alloantibody can occur with help from CD4+ cells, which recognize either donor class II antigens or modified recipient class II antigens; (c) isotype switching from IgM to IgG alloantibody requires help from CD4+ cells activated by antigens presented by recipient MHC class II molecules; and (d) the cytoplasmic domain of the recipient MHC class II molecules may be involved in the mechanism that leads to isotype switching by B cells. Thus, there are two levels of CD4-mediated help available for B cells responding to alloantigens: one (involving a noncognate interaction) can produce B cell activation, and a second (involving a cognate interaction) is required for differentiation and IgG alloantibody production.

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

Nature ◽  
1984 ◽  
Vol 312 (5991) ◽  
pp. 275-277 ◽  
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

scholarly journals Molecular characterization of major histocompatibility complex class II gene expression and demonstration of antigen-specific T cell response indicate a new phenotype in class II-deficient patients.

1995 ◽  
Vol 181 (4) ◽  
pp. 1411-1423 ◽  
Author(s):  
I Hauber ◽  
H Gulle ◽  
H M Wolf ◽  
M Maris ◽  
H Eggenbauer ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Major Histocompatibility Complex ◽  
B Cells ◽  
Mhc Class Ii ◽  
Class Ii ◽  
Specific Protein ◽  
Histocompatibility Complex ◽  
Hla Dr ◽  
Class Ii Antigens

Major histocompatibility complex (MHC) class II deficiency is an inherited autosomal recessive combined immunodeficiency. The disease is known as bare lymphocyte syndrome (BLS). BLS is characterized by a lack of constitutive MHC class II expression on macrophages and B cells as well as a lack of induced MHC class II expression on cells other than professional antigen-presenting cells (APCs) due to the absence of mRNA and protein of the human leukocyte antigen (HLA) class II molecules, designated HLA-DR, -DQ, and -DP. The defect in gene expression is located at the transcriptional level and affects all class II genes simultaneously. Here we have analyzed transcription and protein expression of class II antigens in Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines and mononuclear cells (MNCs) of twin brothers. Whereas flow cytometric analysis failed to detect class II antigens on the cell surface of the patients' EBV-B cells and MNCs, examination of the genes coding for HLA-DR, -DQ, -DP, and the invariant chain (Ii) by reverse transcriptase-polymerase chain reaction amplification resulted in an unusual mRNA pattern in the B cell lines of the patients (HLA-DR alpha +, -DR beta, -DQ alpha +, -DQ beta -, -DP alpha -; -DP beta +, Ii+). In accordance with these findings no HLA-DR beta-specific protein was detected by immunoblotting, whereas low levels of HLA-DR alpha and normal levels of Ii were present. In contrast to EBV-B cells, the MNCs of both patients displayed a residual HLA-DR beta, -DQ beta, and -DP alpha mRNA signal. Furthermore, HLA-DR beta-specific protein was found in addition to HLA-DR alpha by immunoblotting of cell lysates, even though it was clearly decreased as compared with controls. Our results indicate that the defect in class II antigen expression is not necessarily present to the same extent in B cells and cells of other lineages. mRNA levels of HLA-DR beta were found to be enriched in adherent cells within the MNC fraction. Further investigations indicated that the MHC class II expressed is functional in antigen presentation, as the two boys' CD4+ T cells became activated and expressed interleukin-2R after stimulation of peripheral blood mononuclear cell cultures with recall antigen (tetanus toxoid). Furthermore, T cells tested in one of the two patients responded to both MHC class I and II allostimulation, and this response was inhibited by monoclonal antibodies of the respective specificity.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Lenalidomide and Dexamethasone Combination in Patients with Chronic Lymphocytic Leukemia (CLL) Relapsing or Resistant to Treatment (LENDEX-LLC-09): A Gene Expression Profiling Study

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4675-4675
Author(s):  
Anna Puiggros ◽  
Pau Abrisqueta ◽  
Lara Nonell ◽  
Marta Bodalo ◽  
Eulalia Puigdecanet ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Lymphocytic Leukemia ◽  
Down Regulation ◽  
Tnf Α

Abstract Background. Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease in which immune evasion of tumoral cells, as well as, an impaired CD4 and CD8 T-cell function have been described. Immunomodulatory drugs, such as lenalidomide, alone or in combination with other treatments are promising strategies for those patients with refractory disease. The combination of lenalidomide with dexamethasone has been investigated in multiple myeloma and has revealed as a highly efficient treatment. Nonetheless, the efficacy and mechanisms of action of this combination in CLL have not been elucidated. Aim. To assess the effect of lenalidomide and dexamethasone combination in gene expression of CLL B cells, as well as CD4+ and CD8+ T cells from CLL patients enrolled in LENDEX-LLC-09 trial. Methods. Four patients included in the LENDEX-LLC-09 trial (NCT01246557) were studied (2M/2F, med age 72). All presented with advanced CLL (2 B and 2 C Binet stages), and were previously treated by a minimum of two chemo-immunotherapy regimens. Peripheral blood samples were taken at the recruitment and the 7th day of the first cycle of lenalidomide (2.5mg/day) and dexamethasone (20mg/day, 4 days). Total RNA was extracted from CLL B cells (CD5+ CD19+) and T cells (CD4+ or CD8+) positively selected by immunomagnetic methods (Miltenyi Biotec). Good quality RNA (RIN>7) was hybridized to Human Gene 2.0 ST array (Affymetrix). Differences between gene expression of pretreated and treated samples were assessed for each cell type using linear models for microarrays. Genes with a |logFC|>1 were considered as potentially relevant. Functional analysis was performed using Ingenuity Pathway Analysis (IPA). Results and discussion. The major effect in the gene expression due to treatment was observed in CD4+ T cells, which presented 290 up-regulated genes and 103 down-regulated. CLL cells showed up-regulation of 189 and down-regulation of 53 genes, while increase and decrease in the expression of 112 and 37 genes, respectively, were found in CD8+ T cells. Globally, the most important involved networks were related to cell-to-cell signaling, cellular growth and proliferation, cell death and survival, as well as inflammatory response and immune cell trafficking. Regarding CLL B cells, TNF-α was the most up-regulated gene, as previously described in lenalidomide treated B cells. Contrarily, we did not observe significant differences in genes involved in the immunologic synapse, as CD80, CD86, CD200, PD-L1, CD276 and CD270, which have been reported as key regulators in lenalidomide mechanism of action. Of note, a general increase of genes associated with binding to cells (CD68, CTLA4, ADAM28, ITGAX, LY96) was detected. In contrast to previous studies that demonstrated a growth arrest and induction of apoptosis by lenalidomide or dexamethasone in monotherapy (Baptista et al, 2012; Fecteau et al, 2014), a global inhibition of the apoptosis (up-regulation of BTK and CD79B and inhibition of SMAD7, among others) were observed when both drugs were combined. Considering CD8+ T cells gene expression, an up-regulation of genes involved in leukocyte activation and cell-to-cell binding was detected. The most remarkable changes were found in TNF-α and IFN-γ induction, as well as in ADAM28, LY96 and CD68. In contrast to CD8+ T cells, an inhibition of CD4+ T cell proliferation was observed after the combined treatment (up-regulation of VSIG4, LILRB4 and down-regulation of ICOS). This observation suggests that dexamethasone administration inhibits the CD4+ activation promoted by lenalidomide, as has been described in multiple myeloma (Hsu et al, 2011). Regarding response to treatment, two patients initially presented a complete response with positive minimal residual disease. However, all patients finally progressed after treatment and one died due to disease progression. No significant differences in gene expression patterns were found among patients. Conclusions. Our results suggest that lenalidomide and dexamethasone combination leads to an anti-tumoral activity displayed by an activation of CD8+ T cells against the tumor, rather than an increase of apoptosis in CLL cells. More studies are needed to confirm these preliminary findings of the combined effect of lenalidomide and dexamethasone in refractory CLL patients. Acknowledgments. This work was funded by Celgene, and supported by PI11/1621, 14SGR585 and Fundació LaCaixa. Disclosures Off Label Use: Lenalidomide and dexamethasone combination in CLL.

Recognition of MHC Class II Antigens by the CD4: T Cell Receptor Complex

H-2 Antigens ◽  
1987 ◽  
pp. 441-449
Author(s):  
Charles A. Janeway ◽  
Pilar Portoles ◽  
John P. Tite ◽  
Jose Rojo ◽  
Kaj Saizawa ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Cell Receptor ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Receptor Complex ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

T-Cell Proliferation and Expression of MHC Class II Antigens

1984 ◽  
Vol 19 (4) ◽  
pp. 373-377 ◽  
Author(s):  
G. BROWN ◽  
L. WALKER ◽  
N.R. LING ◽  
P. RICHARDSON ◽  
G.D. JOHNSON ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Mhc Class Ii ◽  
Class Ii ◽  
T Cell Proliferation ◽  
Mhc Class Ii Antigens ◽  
Class Ii Antigens

scholarly journals Immunomodulatory effects of different intravenous immunoglobulin preparations in chronic lymphocytic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ana Colado ◽  
Esteban Enrique Elías ◽  
Valeria Judith Sarapura Martínez ◽  
Gregorio Cordini ◽  
Pablo Morande ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Cell Activation ◽  
Cell Activation ◽  
Lymphocytic Leukemia ◽  
Immunomodulatory Effects ◽  
Immunoglobulin Preparations

AbstractHypogammaglobulinemia is the most frequently observed immune defect in chronic lymphocytic leukemia (CLL). Although CLL patients usually have low serum levels of all isotypes (IgG, IgM and IgA), standard immunoglobulin (Ig) preparations for replacement therapy administrated to these patients contain more than 95% of IgG. Pentaglobin is an Ig preparation of intravenous application (IVIg) enriched with IgM and IgA (IVIgGMA), with the potential benefit to restore the Ig levels of all isotypes. Because IVIg preparations at high doses have well-documented anti-inflammatory and immunomodulatory effects, we aimed to evaluate the capacity of Pentaglobin and a standard IVIg preparation to affect leukemic and T cells from CLL patients. In contrast to standard IVIg, we found that IVIgGMA did not modify T cell activation and had a lower inhibitory effect on T cell proliferation. Regarding the activation of leukemic B cells through BCR, it was similarly reduced by both IVIgGMA and IVIgG. None of these IVIg preparations modified spontaneous apoptosis of T or leukemic B cells. However, the addition of IVIgGMA on in vitro cultures decreased the apoptosis of T cells induced by the BCL-2 inhibitor, venetoclax. Importantly, IVIgGMA did not impair venetoclax-induced apoptosis of leukemic B cells. Overall, our results add new data on the effects of different preparations of IVIg in CLL, and show that the IgM/IgA enriched preparation not only affects relevant mechanisms involved in CLL pathogenesis but also has a particular profile of immunomodulatory effects on T cells that deserves further investigation.

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