scholarly journals Reduced Expression of HLA Class II Molecules and Interleukin-10- and Transforming Growth Factor β1-Independent Suppression of T-Cell Proliferation in Human Cytomegalovirus-Infected Macrophage Cultures

2001 ◽  
Vol 75 (11) ◽  
pp. 5174-5181 ◽  
Author(s):  
Jenny Odeberg ◽  
Cecilia Söderberg-Nauclér
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Transforming Growth Factor ◽  
Class Ii ◽  
Interleukin 10 ◽  
Transforming Growth Factor Β1 ◽  
Hla Class Ii ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Hla Class Ii Molecules

ABSTRACT After a primary infection, human cytomegalovirus (HCMV) establishes lifelong latency in myeloid lineage cells, and the virus has developed several mechanisms to avoid immune recognition and destruction of infected cells. In this study, we show that HCMV utilizes two different strategies to reduce the constitutive expression of HLA-DR, -DP, and -DQ on infected macrophages and that infected macrophages are unable to stimulate a specific CD4+ T-cell response. Downregulation of the HLA class II molecules was observed in 90% of the donor samples and occurred in two phases: at an early (1 day postinfection [dpi]) time point postinfection and at a late (4 dpi) time point postinfection. The early inhibition of HLA class II expression and antigen presentation was not dependent on active virus replication, since UV-inactivated virus induced downregulation of HLA-DR and inhibition of T-cell proliferation at 1 dpi. In contrast, the late effect required virus replication and was dependent on the expression of the HCMV unique short (US) genes US1 to -9 or US11 in 77% of the samples. HCMV-treated macrophages were completely devoid of T-cell stimulation capacity at 1 and 4 dpi. However, while downregulation of HLA class II expression was rather mild, a 66 to 90% reduction in proliferative T-cell response was observed. This discrepancy was due to undefined soluble factors produced in HCMV-infected cell cultures, which did not include interleukin-10 and transforming growth factor β1. These results suggest that HCMV reduces expression of HLA class II molecules on HCMV-infected macrophages and inhibits T-cell proliferation by different distinct pathways.

COUNTER-ANTIGEN PRESENTATION: FIBROBLASTS PRODUCE CYTOKINES BY SIGNALLING THROUGH HLA CLASS II MOLECULES WITHOUT INDUCING T-CELL PROLIFERATION

Cytokine ◽  
2002 ◽  
Vol 17 (4) ◽  
pp. 175-181 ◽  
Author(s):  
Hideki Ohyama ◽  
Fusanori Nishimura ◽  
Michio Meguro ◽  
Shogo Takashiba ◽  
Yoji Murayama ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Antigen Presentation ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Proliferation ◽  
Hla Class Ii Molecules

HLA class II molecules on monocytes regulate T cell proliferation through physical interaction in the CD3 activation pathway

1991 ◽  
Vol 21 (1) ◽  
pp. 29-33 ◽  
Author(s):  
Giuseppina Ruggiero ◽  
Luigi Racioppi ◽  
Ciro Manzo ◽  
Giuseppe Pirozzi ◽  
Ugo D'Oro ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Proliferation ◽  
Physical Interaction ◽  
Activation Pathway ◽  
Hla Class Ii Molecules

scholarly journals DQ 65–79, A Peptide Derived from HLA Class II, Mimics p21 to Block T Cell Proliferation

2003 ◽  
Vol 171 (10) ◽  
pp. 5064-5070 ◽  
Author(s):  
Chen Dong ◽  
Shu-Chen Lyu ◽  
Alan M. Krensky ◽  
Carol Clayberger
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Proliferation

scholarly journals Regulatory T Cells Suppress In Vitro Proliferation of Virus-Specific CD8+ T Cells during Persistent Hepatitis C Virus Infection

2005 ◽  
Vol 79 (12) ◽  
pp. 7852-7859 ◽  
Author(s):  
Simon M. Rushbrook ◽  
Scott M. Ward ◽  
Esther Unitt ◽  
Sarah L. Vowler ◽  
Michaela Lucas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Interleukin 10 ◽  
Hcv Infection ◽  
T Cell Proliferation ◽  
Chronic Hcv

ABSTRACT The basis of chronic infection following exposure to hepatitis C virus (HCV) infection is unexplained. One factor may be the low frequency and immature phenotype of virus-specific CD8+ T cells. The role of CD4+CD25+ T regulatory (Treg) cells in priming and expanding virus-specific CD8+ T cells was investigated. Twenty HLA-A2-positive patients with persistent HCV infection and 46 healthy controls were studied. Virus-specific CD8+ T-cell proliferation and gamma interferon (IFN-γ) frequency were analyzed with/without depletion of Treg cells, using peptides derived from HCV, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). CD4+CD25+ Treg cells inhibited anti-CD3/CD28 CD8+ T-cell proliferation and perforin expression. Depletion of CD4+CD25+ Treg cells from chronic HCV patients in vitro increased HCV and EBV peptide-driven expansion (P = 0.0005 and P = 0.002, respectively) and also the number of HCV- and EBV-specific IFN-γ-expressing CD8+ T cells. Although stimulated CD8+ T cells expressed receptors for transforming growth factor beta and interleukin-10, the presence of antibody to transforming growth factor beta and interleukin-10 had no effect on the suppressive effect of CD4+CD25+ regulatory T cells on CD8+ T-cell proliferation. In conclusion, marked CD4+CD25+ regulatory T-cell activity is present in patients with chronic HCV infection, which may contribute to weak HCV-specific CD8+ T-cell responses and viral persistence.

scholarly journals Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression.

1991 ◽  
Vol 174 (4) ◽  
pp. 915-924 ◽  
Author(s):  
R de Waal Malefyt ◽  
J Haanen ◽  
H Spits ◽  
M G Roncarolo ◽  
A te Velde ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cell ◽  
T Cell Responses ◽  
Class Ii ◽  
Interleukin 10 ◽  
T Cell Proliferation ◽  
Tnf Alpha ◽  
Cell Responses ◽  
Cell Clones ◽  
Antigen Presenting

Interleukin 10 (IL-10) and viral IL-10 (v-IL-10) strongly reduced antigen-specific proliferation of human T cells and CD4+ T cell clones when monocytes were used as antigen-presenting cells. In contrast, IL-10 and v-IL-10 did not affect the proliferative responses to antigens presented by autologous Epstein-Barr virus-lymphoblastoid cell line (EBV-LCL). Inhibition of antigen-specific T cell responses was associated with downregulation of constitutive, as well as interferon gamma- or IL-4-induced, class II MHC expression on monocytes by IL-10 and v-IL-10, resulting in the reduction in antigen-presenting capacity of these cells. In contrast, IL-10 and v-IL-10 had no effect on class II major histocompatibility complex (MHC) expression on EBV-LCL. The reduced antigen-presenting capacity of monocytes correlated with a decreased capacity to mobilize intracellular Ca2+ in the responder T cell clones. The diminished antigen-presenting capacities of monocytes were not due to inhibitory effects of IL-10 and v-IL-10 on antigen processing, since the proliferative T cell responses to antigenic peptides, which did not require processing, were equally well inhibited. Furthermore, the inhibitory effects of IL-10 and v-IL-10 on antigen-specific proliferative T cell responses could not be neutralized by exogenous IL-2 or IL-4. Although IL-10 and v-IL-10 suppressed IL-1 alpha, IL-1 beta, tumor necrosis factor alpha (TNF-alpha), and IL-6 production by monocytes, it was excluded that these cytokines played a role in antigen-specific T cell proliferation, since normal antigen-specific responses were observed in the presence of neutralizing anti-IL-1, -IL-6, and -TNF-alpha mAbs. Furthermore, addition of saturating concentrations of IL-1 alpha, IL-1 beta, IL-6, and TNF-alpha to the cultures had no effect on the reduced proliferative T cell responses in the presence of IL-10, or v-IL-10. Collectively, our data indicate that IL-10 and v-IL-10 can completely prevent antigen-specific T cell proliferation by inhibition of the antigen-presenting capacity of monocytes through downregulation of class II MHC antigens on monocytes.

Modification of Invariant Chain and CLIP Expression Increases the Immunogenicity of Leukemic Blasts to Potentiate Leukemia-Specific T Cell Reactivity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5430-5430
Author(s):  
Marvin M. van Luijn ◽  
Martine E.D. Chamuleau ◽  
James A. Thompson ◽  
Suzanne Ostrand-Rosenberg ◽  
Theresia M. Westers ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cd4 T Cell ◽  
T Cell Proliferation ◽  
Invariant Chain ◽  
Hla Dr

Abstract In patients suffering from AML, disease progression could be explained by the ability of leukemic blasts to escape immune surveillance. Since CD4+ T cells are indispensable for generating effective anti-leukemic immune responses, escaping leukemic blasts might exhibit aberrant HLA class II antigen presentation that interferes with antigen-specific CD4+ T cell activation. The Invariant Chain (Ii) is essentially involved in HLA class II processing, since it blocks endogenous antigen loading of HLA class II in the endoplasmic reticulum and mediates its transport to the lysosomal exogenous antigen-loading compartments. We previously showed that increased expression of the class II-associated invariant chain peptide (CLIP), a small remnant of Ii, on AML blasts predicts poor clinical outcome [Chamuleau et al., Cancer Research2004; 64]. This study was undertaken to modulate Ii and CLIP expression of leukemic blasts and examine the impact on leukemia-specific CD4+ T cell recognition. The THP-1 and Kasumi-1 AML cell lines were selected for Ii and CLIP modulation based upon their flow cytometrically determined DR+CLIP+Ii+ immunophenotype. Retroviral transduction of both THP-1 and Kasumi-1 with specific Ii siRNAs led to a clear decline in Ii expression, as MFI values dropped from 4.5 to 1.4 and 13.5 to 0.9, respectively, 6 weeks after transduction. Interestingly, the effect of Ii down-modulation on CLIP and HLA-DR expression levels differed between THP-1 and Kasumi-1 blasts. In THP-1, Ii down-modulation resulted in reduced CLIP expression (MFI values decreased from 35.9 to 14.0), while HLA-DR expression levels remained relatively constant. This yielded a marked reduction in the relative amount of CLIP presented by DR (decline from 1.12 to 0.52). In Kasumi-1, both CLIP and DR levels were markedly decreased by Ii down-modulation (MFI values declined from respectively 35.5 to 2.7 and 24.6 to 3.7). Although total DR expression was already reduced, the relative amount of CLIP presented by DR was even further reduced (decline from 1.49 to 0.78). These results might indicate that Ii and CLIP down-modulation enables HLA class II presentation of leukemia-associated antigens on these blast cell lines. Subsequently, DR+CLIP+Ii+ and DR+CLIP−Ii− blasts were compared in their capacity to induce allogeneic CD4+ T cell proliferation in mixed leukocyte reactions (MLRs). CD4+ T cells were obtained from different healthy donors and cultured in triplicate with irradiated blasts at various stimulator-to-responder (S/R) ratios. MLRs consisting of DR+CLIP−Ii− THP-1 blasts showed marked increases in CD4+ T cell proliferation in a S/R dependent manner compared to MLRs performed with DR+CLIP+Ii+ THP-1 blasts. These increases in CD4+ T cell proliferation (maximal 4.5-fold) correlated strongly with the decreased relative CLIP/DR amounts on THP-1 transductants. Similar increases in CD4+ T cell proliferation were observed when DR+CLIP−Ii− Kasumi-1 blasts were used as stimulator cells, also clearly correlating with the accompanying relative CLIP/DR amounts. The DR-specific L243 antibody totally abrogated CD4+ T cell proliferation, confirming HLA-DR restriction of the proliferative responses. These data demonstrate an essential role for Ii and CLIP expression of AML blasts in modifying T cell responsiveness and introduce Ii down-modulation as a potential immunotherapeutic strategy to activate leukemia-specific CD4+ T cells.

Monoclonal antibody OKT3-induced T cell proliferation: Differential role of HLA class II determinants expressed by T cells and monocytes

1990 ◽  
Vol 125 (1) ◽  
pp. 79-91 ◽  
Author(s):  
Ciro Manzo ◽  
Giuseppina Ruggiero ◽  
Luigi del Vecchio ◽  
Luigi Racioppi ◽  
Giuseppe Pirozzi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Proliferation

Inhibition by anti-HLA class II monoclonal antibodies of monocyte-dependent T cell proliferation induced by monoclonal antibody OKT3

1987 ◽  
Vol 17 (11) ◽  
pp. 1585-1592 ◽  
Author(s):  
Giuseppina Ruggiero ◽  
Ciro Manzo ◽  
Silvia Fontana ◽  
Giuseppe Scala ◽  
Giuseppe Pirozzi ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Proliferation ◽  
Monoclonal Antibodies ◽  
T Cell ◽  
Class Ii ◽  
Hla Class Ii ◽  
T Cell Proliferation

scholarly journals T-cell mediated autoimmunity to the insulinoma-associated protein 2 islet tyrosine phosphatase in type 1 diabetes mellitus

1999 ◽  
pp. 272-278 ◽  
Author(s):  
F Dotta ◽  
S Dionisi ◽  
V Viglietta ◽  
C Tiberti ◽  
MC Matteoli ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Type 1 Diabetes ◽  
T Cell ◽  
T Lymphocyte ◽  
Tyrosine Phosphatase ◽  
T Cell Response ◽  
T Cell Proliferation ◽  
Diabetic Patients ◽  
Hla Dr

The target molecules of the T-cell response in type 1 diabetes, despite their pathogenic importance, remain largely uncharacterized, especially in humans. Interestingly, molecules such as insulin and glutamic acid decarboxylase (GAD) have been shown to be a target not only of autoantibodies, but also of autoreactive T-lymphocytes both in man and in the non-obese diabetic (NOD) mouse. In the present study we aimed to determine the existence of a specific T-cell response towards the insulinoma-associated protein 2 (IA-2) islet tyrosine phosphatase, a recently identified autoantigen which is the target of autoantibodies strongly associated with diabetes development. Human recombinant IA-2 produced in Escherichia coli, was tested for its reactivity with peripheral blood lymphocytes obtained from 16 newly diagnosed type 1 diabetic patients and from 25 normal controls, 15 of whom were HLA-DR-matched. A T-cell proliferation assay was performed in triplicate employing freshly isolated cells in the absence or in the presence of the antigen to be tested (at two different concentrations: 2 microg/ml and 10 microg/ml). A specific T-cell proliferation (defined as a stimulation index (S.I.) >/=3) was observed against IA-2 used at a concentration of 10 microg/ml (but not of 2 microg/ml) in 8/16 diabetic patients, in 1/15 HLA-DR-matched control subjects (P<0.01 by Fisher exact test) and in 0/10 of the remaining normal individuals. A statistically significant difference (P<0.003 by Mann-Whitney U test) was also observed in S.I. values between patients (3.1+/-1.4) and HLA-DR-matched controls (1.7+/-0.54) employing IA-2 at a concentration of 10 microg/ml. However, when IA-2 was used at a concentration of 2 microg/ml, the difference in S. I. between patients (1.65+/-0.8) and controls (1.0+/-0.3) did not reach statistical significance. In conclusion, these data show the presence of a specific, dose-dependent T-lymphocyte response against the IA-2 islet tyrosine phosphatase at the onset of type 1 diabetes. Consequently, this molecule appears to be a target not only at the B-lymphocyte but also at the T-lymphocyte level, reinforcing the potential pathogenic role of this autoantigen in the islet destructive process.

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