scholarly journals CD85/LIR-1/ILT2 and CD152 (Cytotoxic T Lymphocyte Antigen 4) Inhibitory Molecules Down-Regulate the Cytolytic Activity of Human CD4+ T-Cell Clones Specific forMycobacterium tuberculosis

2001 ◽  
Vol 69 (10) ◽  
pp. 6022-6029 ◽  
Author(s):  
Andrea Merlo ◽  
Daniele Saverino ◽  
Claudya Tenca ◽  
Carlo Enrico Grossi ◽  
Silvia Bruno ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Cytolytic T Lymphocytes ◽  
T Cell Clones ◽  
Lymphocyte Antigen ◽  
Cell Clones ◽  
Inhibitory Molecules

ABSTRACT Antigen-specific cytolytic CD4+ T lymphocytes controlMycobacterium tuberculosis infection by secreting cytokines and by killing macrophages that have phagocytosed the pathogen. However, lysis of the latter cells promotes microbial dissemination, and other macrophages engulf the released bacteria. Subsequently, CD4+ T-cell-mediated killing of macrophages goes on, and this persistent process may hamper control of infection, unless regulatory mechanisms maintain a subtle balance between lysis of macrophages by cytolytic CD4+ cells and activation of cytolytic CD4+ cells by infected macrophages. We asked whether inhibitory molecules expressed by CD4+ cytolytic T lymphocytes could play a role in such a balance. To this end, human CD4+ T-cell clones specific for M. tuberculosis were produced that displayed an autologous major histocompatibility complex class II-restricted lytic ability against purified protein derivative (PPD)-pulsed antigen-presenting cells. All T-cell clones expressed CD152 (cytotoxic T-lymphocyte antigen 4 [CTLA-4]) and CD85/leukocyte immunoglobulin-like receptor 1 (LIR-1)/immunoglobulin-like transcript 2 (ILT2) inhibitory receptors, but not CD94 and the killer inhibitory receptor (or killer immunoglobulin-like receptor [KIR]) p58.2. CD3-mediated activation of the clones was inhibited in a redirected killing assay in which CD152 and CD85/LIR-1/ILT2 were cross-linked. Specific antigen-mediated proliferation of the clones was also sharply reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked by specific monoclonal antibody (MAb) followed by goat anti-mouse antiserum. In contrast, blockade of the receptors by specific MAb only increased their proliferation. Production of interleukin 2 (IL-2) and gamma interferon (IFN-γ) by the T-cell clones was also strongly reduced when CD152 and CD85/LIR-1/ILT2 were cross-linked. The lytic activity of the T-cell clones against PPD-pulsed autologous monocytes or Epstein-Barr virus-activated B cells was increased by blockade and decreased by cross-linking of the receptors. These results indicate that CD152 and CD85/LIR-1/ILT2 play a role in the regulation of the antigen-specific activity of CD4+ cytolytic T lymphocytes against PPD-presenting cells.

Gene Expression Profiling of the Clinical Significant CD57+CD8+ Cytotoxic T Cell Expansions in Patients with Waldenstrom’s Macroglobulinemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3395-3395
Author(s):  
Daniel Sze ◽  
Tetsuo Yamagishi ◽  
Warren Kaplan ◽  
Ross D. Brown ◽  
Phoebe Joy Ho ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Target Cell ◽  
Peripheral Blood ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Clones ◽  
Cell Clones ◽  
Lymphocyte Cell

Abstract Previous studies have suggested that expanded T-cell clones are found in the blood of 59% of patients with multiple myeloma. These expanded T-cell clones are associated with prolonged overall survival and thus it has been suggested that they may have anti-tumor activity. We have previously reported similar T-cell clones exist in the peripheral blood of patients with Waldenstrom’s Macroglobulinemia (WM) by using flow cytometry to determine the T cell receptor (TCR) Vβ repertoire. Expanded T-cell clones were detected in 9 of 15 (60%) patient samples. Of the nine patients with TCR Vβ clones, four patients had multiple clones. The TCR Vβ clones were not identical, representing a variety of families across the TCR Vβ repertoire. We have previously found that while the TCRVβ+CD8+CD57 negative subset represents polyclonal populations, the CD57 positive subset represents either monoclonal or biclonal populations. By comparing the genetic profiling of these two subsets from a statistically significant gene list, two genes have been found to be highly upregulated in the CD57 negative polyclonal subset. These two genes are i.) SESN3, a member in the Sorting Nexin (SNX) protein family which is implicated in regulating membrane traffic capable of interaction with phosphatidylinositol-3-phosphate (10.4 fold, p=0.0241); ii.) Epstein-Barr virus induced gene 2 (lymphocyte-specific G protein-coupled receptor) EBI2 (7.4 fold, p=0.0207): This finding is in contrast to previous report that EBI2 is expressed in B-lymphocyte cell lines and in lymphoid tissues but not in T-lymphocyte cell lines or peripheral blood T lymphocytes. For the CD57 positive clonal T cell expansions, consistent with our previous reports, CD28 expression was found to be down regulated by 2.6 fold. There are two genes found to be highly upregulated. They are i.) Granzyme B (4.3 fold, p=0.0337) also called Cytotoxic T-lymphocyte proteinase 2. This enzyme is necessary for target cell lysis in cell-mediated immune responses through caspase-dependent apoptosis; ii.) Granzyme H, also called Cytotoxic T-lymphocyte proteinase and probably necessary for target cell lysis in cell-mediated immune responses. In summary, we have shown that CD57 positive clonal T cell populations exist in some patients with WM. Importantly, microarray results have indicated some genes and proteins that may related to better patients survival as previously demonstrated in patients with Multiple Myeloma.

scholarly journals Cytotoxic T Lymphocyte Antigen 4 (Ctla-4) Engagement Delivers an Inhibitory Signal through the Membrane-Proximal Region in the Absence of the Tyrosine Motif in the Cytoplasmic Tail

1999 ◽  
Vol 190 (6) ◽  
pp. 765-774 ◽  
Author(s):  
Chiaki Nakaseko ◽  
Shoichiro Miyatake ◽  
Tomohiko Iida ◽  
Satoru Hara ◽  
Ryo Abe ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
Cytoplasmic Tail ◽  
Proximal Region ◽  
Lymphocyte Antigen ◽  
Membrane Proximal Region

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a T cell costimulation receptor that delivers inhibitory signals upon activation. Although the tyrosine-based motif (165YVKM) within its cytoplasmic tail has been shown to associate in vitro with Src homology 2 domain–containing tyrosine phosphatase (SHP-2) and phosphatidylinositol 3 kinase upon phosphorylation, the mechanism of negative signaling remains unclear. Here, we report a new mechanism of negative signaling based on the analysis of murine T cell clones transfected with various mutants of CTLA-4. Upon T cell activation by cross-linking with anti-CD3 and anti-CD28 antibodies, CTLA-4 engagement inhibited both proliferation and interleukin 2 production in tyrosine mutants as well as in wild-type CTLA-4 transfectants. Furthermore, the mutant CTLA-4 lacking most of the cytoplasmic region strongly suppressed interleukin 2 production as well. These data suggest that negative signals by CTLA-4 could be mediated through the membrane-proximal region of CTLA-4 but not through the YVKM motif and that the association of CTLA-4 with SHP-2 is not required for CTLA-4–mediated suppression of T cell activation.

scholarly journals Cytotoxic T Lymphocyte Antigen Costimulation Influences T-Cell Activation in Response to Cryptococcus neoformans

2001 ◽  
Vol 69 (3) ◽  
pp. 1508-1514 ◽  
Author(s):  
Donatella Pietrella ◽  
Stefano Perito ◽  
Francesco Bistoni ◽  
Anna Vecchiarelli
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cryptococcus Neoformans ◽  
T Cell Activation ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 2 ◽  
T Cell Response ◽  
Lymphocyte Antigen

ABSTRACT The kinetics of cytotoxic T lymphocyte antigen 4 (CTLA-4) expression on T cells responding to Cryptococcus neoformansand its role in regulating the T-cell response were examined. Using peripheral blood mononuclear cells stimulated with encapsulated or acapsular C. neoformans we showed that (i) the encapsulated strain augmented CTLA-4 expression on the T-cell surface while the acapsular strain was a weaker modulator, (ii) CTLA-4 molecules were rapidly up-regulated after the addition of encapsulated C. neoformans, (iii) CTLA-4 was up-regulated predominantly in CD4+ T cells responding to C. neoformans, and (iv) blockage of CTLA-4 with (Fab′)2 of monoclonal antibody to CTLA-4 induced T-cell proliferation that paralleled the enhancement of interleukin-2 and gamma interferon production. These results suggest that capsular material, the major virulence factor of C. neoformans, promotes synthesis and expression of CTLA-4 molecules predominantly in CD4+ T cells. CTLA-4-mediated deactivation is due not to lack of costimulation but to specific recognition of CTLA-4 for B7 molecules. This appears to be a new mechanism by whichC. neoformans may elude the host immune response.

scholarly journals Self-sparing of long-term in vitro-cloned or uncloned cytotoxic T lymphocytes.

1986 ◽  
Vol 164 (3) ◽  
pp. 962-967 ◽  
Author(s):  
M F Luciani ◽  
J F Brunet ◽  
M Suzan ◽  
F Denizot ◽  
P Golstein
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cytotoxic T Cell ◽  
Cell Populations ◽  
Con A ◽  
T Cell Clones ◽  
Cell Clones

At least some long-term in vitro-cultured cytotoxic T cell clones and uncloned cell populations are able, in the presence of Con A, to lyse other cells, to be lysed by other cells, but not to lyse themselves. This as-yet-unexplained result may have implications as to the mechanism of T cell-mediated cytotoxicity.

scholarly journals Clonal analysis of bcr-abl rearrangement in T lymphocytes from patients with chronic myelogenous leukemia

Blood ◽  
1992 ◽  
Vol 79 (4) ◽  
pp. 1017-1023 ◽  
Author(s):  
D Jonas ◽  
M Lubbert ◽  
ES Kawasaki ◽  
M Henke ◽  
KJ Bross ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
T Lymphocytes ◽  
Chronic Myelogenous Leukemia ◽  
Philadelphia Chromosome ◽  
Precursor Cell ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
T Cell Clones ◽  
Cell Clones

The cytogenetic hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph1), which reflects a chromosomal translocation t(9;22) and a rearrangement of the ABL and bcr genes. This marker is found in all cells arising from the same malignant precursor cell and can be detected in CML cells of the myeloid, monocytic, erythroid, and B-lymphocyte lineage. It is, however, controversial as to whether T lymphocytes of CML patients carry this gene rearrangement. An answer to this question would clarify whether the translocation in CML occurs in a pluripotent hematopoietic stem cell or in a precursor cell already committed to certain lineages, but not the T-cell lineage. To address this question, we established T-cell clones from peripheral venous blood cells of four patients with CML and screened these clones for bcr-abl fusion transcripts by means of polymerase chain reaction and Southern blot analysis. In four T-cell clones of three of these patients, the bcr-abl transcript could be detected. None of 12 T-cell clones of the fourth patient disclosed detectable bcr-abl amplification product. Both CD4+ as well as CD8+ clones displayed fused bcr-abl sequences. These data imply that in CML some but not all T lymphocytes may originate from the Ph1-positive stem cell.

Diminished Production of Interleukin 2 and Gamma-Interferon by Cloned «T» Cells from Patients with the Acquired Immunodeficiency Syndrome (AIDS)

1987 ◽  
Vol 73 (3) ◽  
pp. 273-278 ◽  
Author(s):  
Enrico Maggi ◽  
Donatella Macchia ◽  
Paola Parronchi ◽  
Domenico Milo ◽  
Sergio Romagnani
Keyword(s):  
T Cells ◽  
T Cell ◽  
Interleukin 2 ◽  
Immune Deficiency Syndrome ◽  
Gamma Interferon ◽  
Aids Patients ◽  
T Cell Clones ◽  
Cell Clones ◽  
The Mean ◽  
Mean Concentration

A total of 76 T-cell clones established from peripheral blood (PB) of 2 patients with the acquired immune deficiency syndrome (AIDS) and of 141 T-cell clones established from PB of 3 normal donors were compared for their ability to produce interleukin 2 (IL-2) and gamma-interferon (γ-IFN). Twenty-seven clones from AIDS patients and 85 clones from controls expressed the CD4 phenotype, whereas 49 clones from AIDS patients and 56 clones from controls expressed the CD8 phenotype. There were no significant differences in the proportions of IL-2-producing CD4 T-cell clones established from PB of patients with AIDS and controls, but the mean concentration of IL-2 produced by CD4 clones from AIDS patients was significantly lower than that produced by CD4 clones from controls. Both the proportion of γ-IFN-producing CD4 clones and the mean concentration of γ-IFN produced by CD4 clones were significantly lower in AIDS patients than in controls. In contrast, there were no differences between AIDS patients and normal individuals in the proportion of IL-2- or Y-IFN-producing CD8 clones, or in the mean concentration of IL-2 and v-IFN produced by CD8 clones. These data suggest that the reduced ability of PB T-cells from patients with AIDS to produce IL-2 and v-IFN is not simply due to altered proportions or numbers of T-cell sub-populations, but also reflects intrinsic abnormalities of individual CD4 T lymphocytes.

scholarly journals Dengue virus-specific human T cell clones. Serotype crossreactive proliferation, interferon gamma production, and cytotoxic activity.

1989 ◽  
Vol 170 (3) ◽  
pp. 763-775 ◽  
Author(s):  
I Kurane ◽  
A Meager ◽  
F A Ennis
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Dengue Virus ◽  
Cytotoxic Activity ◽  
Virus Infections ◽  
Ifn Gamma ◽  
T Cell Clones ◽  
Secondary Infections ◽  
Cell Clones ◽  
Proliferation Assays

The severe complications of dengue virus infections, hemorrhagic manifestation and shock, are much more commonly observed during secondary infections caused by a different serotype of dengue virus than that which caused the primary infections. It has been speculated, therefore, that dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are caused by serotype crossreactive immunopathological mechanisms. We analyzed clones of dengue serotype crossreactive T lymphocytes derived from the PBMC of a donor who had been infected with dengue 3 virus. These PBMC responded best to dengue 3 antigen, but also responded to dengue 1, 2, and 4 antigens, in bulk culture proliferation assays. 12 dengue antigen-specific clones were established using a limiting dilution technique. All of the clones had CD3+ CD4+ CD8 phenotypes. Eight clones responded to dengue 1, 2, 3, and 4 antigens and are crossreactive, while four other clones responded predominantly to dengue 3 antigen. These results indicate that the serotype crossreactive dengue-specific T lymphocyte proliferation observed in bulk cultures reflects the crossreactive responses detected at the clonal level. Serotype crossreactive clones produced high titers of IFN-gamma after stimulation with dengue 3 antigens, and also produced IFN-gamma to lower levels after stimulation with dengue 1, 2, and 4 antigens. The crossreactive clones lysed autologous lymphoblastoid cell line (LCL) pulsed with dengue antigens, and the crossreactivity of CTL lysis by T cell clones was consistent with the crossreactivity observed in proliferation assays. Epidemiological studies have shown that secondary infections with dengue 2 virus cause DHF/DSS at a higher rate than the other serotypes. We hypothesized that the lysis of dengue virus-infected cells by CTL may lead to DHF/DSS; therefore, the clones were examined for cytotoxic activity against dengue 2 virus-infected LCL. All but one of the serotype crossreactive clones lysed dengue 2 virus-infected autologous LCL, and they did not lyse uninfected autologous LCL. The lysis of dengue antigen-pulsed or virus-infected LCL by the crossreactive CTL clones that we have examined is restricted by HLA DP or DQ antigens. These results indicate that primary dengue virus infections induce predominantly crossreactive memory CD4+ T lymphocytes. These crossreactive T lymphocytes proliferate and produce IFN-gamma after stimulation with a virus strain of another serotype, and demonstrate crossreactive cyotoxic activity against autologous cells infected with heterologous dengue viruses.(ABSTRACT TRUNCATED AT 400 WORDS)

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