scholarly journals ALLOANTISERUM-INDUCED INHIBITION OF IMMUNE RESPONSE GENE PRODUCT FUNCTION

1974 ◽  
Vol 139 (3) ◽  
pp. 679-695 ◽  
Author(s):  
Ethan M. Shevach ◽  
Ira Green ◽  
William E. Paul
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Glutamic Acid ◽  
Gene Product ◽  
Lymphoid Cells ◽  
Immune Response Gene ◽  
Ga Response ◽  
Ir Genes

It has been previously demonstrated that alloantisera can specifically block the activation of T lymphocytes by antigens, the response to which is linked to the presence of histocompatibility (H) types against which the alloantisera are directed. Thus, strain 13 anti-2 serum can inhibit the activation of (2 x 13)F1 T lymphocytes by a DNP derivative of a copolymer of L-glutamic acid and L-lysine (DNP-GL), an antigen the response to which is controlled by a 2-linked Ir gene. It was proposed that alloantisera can inhibit T-lymphocyte antigen recognition through interference with the activity of immune response (Ir) gene products. In order to further study whether the inhibitory antibodies within the alloantisera are directed against H antigens or against the products of the Ir genes, we have examined whether the anti-2 serum can inhibit the function of an Ir gene (the L-glutamic acid and L-alanine [GA] gene), which is normally linked to strain 2 H genes when this gene occurs in an outbred animal lacking strain 2 H genes. In the majority of cases, the anti-2 serum was capable of inhibiting the in vitro proliferative response to GA of T cells derived from animals that were GA+2+, but the serum had little if any effect on the GA response of T cells from GA+2- animals. Furthermore, an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2- outbred animal was devoid of inhibitory activity on the GA response of cells from a (2 x 13)F1, while an antiserum prepared in strain 13 animals against the lymphoid cells of a GA+2+ outbred animal was capable of specifically inhibiting the response to GA. It thus appears that the inhibition of the GA response by the anti-2 serum is primarily mediated via antibodies directed toward strain 2 H antigens rather than antibodies specific for the product of the GA Ir gene. The mechanism of alloantiserum induced suppression of Ir gene function would then be by steric interference with the Ir gene product on the cell surface, rather than by direct binding to it. This conclusion implies that the products of both the H genes and the Ir genes are physically related on the cell surface. The implications of such a relationship in terms of the fluid-mosaic model of the lymphocyte surface are discussed.

Specific features of T- and NK-cellular immunity in chronic lymphocytic leukemia

2021 ◽  
Vol 66 (6) ◽  
pp. 345-352
Author(s):  
Evgeniy Vladimirovich Pochtar ◽  
S. A. Lugovskaya ◽  
E. V. Naumova ◽  
E. A. Dmitrieva ◽  
A. I. Kostin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
T Lymphocytes ◽  
Nk Cells ◽  
Lymphocytic Leukemia ◽  
Positive Trend ◽  
Functional Changes ◽  
Activated T Lymphocytes ◽  
T Helpers

Profound immunological dysfunction is the key factor determining the development of infectious complications in chronic lymphocytic leukemia (CLL). The aim of this work is to assess the features of the subpopulation composition of T-lymphocytes (T-helpers (Th), cytotoxic T-lymphocytes (Tcyt), T regulatory cells (Treg), T-NK cells, naive Th, Th-memory, activated T-lymphocytes, TCRγδ cells) and NK cells in peripheral blood of patients with newly diagnosed chronic lymphocytic leukemia (CLL) and receiving ibrutinib therapy. Hematological and immunophenotypic studies have been performed in 30 patients with previously untreated CLL, 122 patients on ibrutinib therapy and 20 healthy donors. The subpopulation composition of T-lymphocytes (Th, Tcyt, Treg, T-NK, naive T-helpers, memory T-helpers, TCRγδ cells, activated T-lymphocytes) and NK cells has been assessed on flow cytometer (FACSCanto II (BD)) using the following panel of monoclonal antibodies: CD45, CD19, CD3, CD4, CD5, CD8, TCRγδ, CD127, CD16, CD56, CD57 CD45RA, CD45R0, HLA-DR, CD25. Compared to controls all CLL samples were found to have higher the absolute number of T-lymphocytes, NK cells and their subpopulations, T-helpers (especially of memory T-cells), cytotoxic T-cells, regulatory T-cells, TCRγδ T-cells, activated T-lymphocytes, increased cytotoxic potential of NK cells in previously untreated CLL patients. Patients who received ibrutinib therapy have registered a positive trend towards recovery of the subpopulation composition of T-lymphocytes and NK-cells. CLL patients have been found to have quantitative and functional changes in the subpopulations of T-lymphocytes and NK cells, indicating dysregulation of the immune response, and a high risk of developing infections. Monitoring of immunological parameters for ibrutinib therapy make possible to estimate impact of ibrutinib on the adaptive anti-CLL immune response.

Insights into the ontogeny and activation of T cells

1994 ◽  
Vol 40 (11) ◽  
pp. 2128-2131 ◽  
Author(s):  
T W Mak
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Immune Responses ◽  
Tyrosine Phosphatase ◽  
T Cell Development ◽  
Cell Development ◽  
Mutant Mice ◽  
Target Cells

Abstract T lymphocytes recognize antigen peptides and major histocompatibility complex products through their T-cell antigen receptors (TcR), consisting of alpha and beta chains. The interaction between T cells and their target cells or antigen-presenting cells is also assisted by a series of other cell-surface polypeptides, most notably CD4 and CD8, which are selectively expressed on mature helper/inducer and killer/suppressor T cells, respectively. Upon engagement of their ligands, a series of signals is transduced intracytoplasmically via some of these molecules and their associated proteins. Perhaps the most important enzyme in this signal transduction process is the lymphocyte-specific tyrosine kinase lck. Another important component is the cell-surface tyrosine phosphatase CD45. This molecule is alternatively spliced and the different isoforms are expressed on the various hematopoietic and lymphopoietic cells. Signaling through the TcR-CD4 D8-lck-CD45 complex is thought to be insufficient to activate T lymphocytes. A costimulatory signal is believed to be essential, and many investigators have suggested that CD28, a ligand for B7/BB1, is such a signal. Immune responses are also controlled by a number of cytokines and soluble factors. Signaling through the tumor necrosis factor receptor p55 is required for clearance of intracellular pathogens. Transcriptional factors involved in controlling interferon production are also important in T-cell development and immune responses. In an attempt to gain a better understanding of the roles of these molecules in T-lymphocyte functions and ontogeny, we generated a series of mutant mice with disruptions in the genes coding for these molecules. We are analyzing the mutant mice to evaluate the importance of these genes in T-cell development.

scholarly journals Phenotypic characterization of human cytolytic T lymphocytes in mixed lymphocyte culture.

1981 ◽  
Vol 153 (1) ◽  
pp. 213-218 ◽  
Author(s):  
A Moretta ◽  
M C Mingari ◽  
B F Haynes ◽  
R P Sekaly ◽  
L Moretta ◽  
...  
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Mixed Lymphocyte Reaction ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Phenotypic Characterization ◽  
Cytolytic T Lymphocytes ◽  
Activated T Cells

Mixed lymphocyte reaction (MLR)-activated T cells were analyzed according to the expression of various cell surface markers by the specific cytotoxic T lymphocytes (CTL) generated in the MLR. CTL were found exclusively in a population of MLR-activated T cells that lacked detectable Fc gamma R but that expressed a surface antigen recognized by the 4F2 monoclonal antibody. In contrast, CTL were found in both the Ia-positive and Ia-negative cells after MLR activation. Thus, the specific CTL generated in the allogeneic MLR can be identified and isolated by virtue of the expression of a particular cell surface marker.

scholarly journals GENETIC CONTROL OF THE IMMUNE RESPONSE

1972 ◽  
Vol 136 (5) ◽  
pp. 1195-1206 ◽  
Author(s):  
John C. Ordal ◽  
F. Carl Grumet
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Genetic Control ◽  
Antibody Production ◽  
Lymphoid Cells ◽  
Antigen Challenge ◽  
Graft Versus Host ◽  
K Cells

The transfer of parental (H-2k/k) nonresponder lymphoid cells into heterozygous (H-2k/q) nonresponder recipients at the time of primary challenge with aqueous poly-L(Tyr,Glu)-poly-D,L-Ala-poly-L-Lys [(T,G)-A--L] elicited the production of both IgM and IgG anti-(T,G)-A--L antibody. Normally, the production of IgG anti-(T,G)-A--L antibody is restricted to strains possessing the responder Ir-1 allele. The timing and intensity of the graft-versus-host (GVH) reaction required for this effect were found to be critical. Injection of H-2k/k cells into H-2k/q recipients 1 wk before antigen challenge did not elicit IgG anti-(T,G)-A--L antibody production, and markedly suppressed IgM anti-(T,G)-A--L antibody production. The transfer of alloimmune (H-2q-primed) H-2k/k cells at the time of antigen challenge was also associated with no IgG and little IgM anti-(T,G)-A--L antibody production. These data are consistent with the model that nonresponder thymus-derived lymphocytes (T cells) activated in a GVH reaction can substitute for (T,G)-A--L-reactive T cells to induce a shift from IgM to IgG anti-(T,G)-A--L antibody production.

scholarly journals Study of the cells proliferating in parent versus F hybrid mixed lymphocyte culture.

1975 ◽  
Vol 141 (4) ◽  
pp. 775-787 ◽  
Author(s):  
P F Piguet ◽  
H K Dewey ◽  
P Vassalli
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Lymphocytes ◽  
Hybrid Cell ◽  
Mixed Lymphocyte Culture ◽  
Lymphocyte Culture ◽  
Lymphoid Cells ◽  
Spleen Cells ◽  
F1 Hybrid ◽  
Proliferation And Differentiation

Caryotypic analysis of the cells dividing in mouse parent-hybrid MLC showed an F1 hybrid cell proliferation, which varied depending upon the source of lymphoid cells used: strong in spleen MLC (sometimes equal to that of the parental cells), less marked in lymph node cell MLC, and most often absent in MLC between cortisone-resistant (CR) thymocytes. MLC between parental spleen cells and F1 CR thymocytes showed, however, that in certain conditions of culture F thymocytes can also proliferate. Using parental or F1 spleen cells lacking T lymphocytes, it was found that F1 cell proliferation is entirely dependent upon the presence of parental T cells, but does not require the presence of T lymphocytes among the F1 cells. Immunofluorescence analysis of the blasts observed in one-way MLC showed that about 70% of the parental blasts were T blasts, and 25%B blasts (containing a high proportion of plasmablasts); among the F1 blasts, there was also the same percentage of B blasts and plasmablasts, but many of the T blasts bore only small amounts of T-cell antigen (MTLA), and there was also about 20%of unstained blasts, possibly T blasts bearing MTLA in amounts undetectable by immunofluorescence. The possibility is discussed that the F1 responding T cells belong to a subpopulation performing a suppressive function; MLC lacking F1 T cells showed increased [3H] thymidine incorporation. The proliferation and differentiation of parental and F1 B cells may result mainly from an unspecific, "polyclonal" triggering.

scholarly journals Cytotoxic CD8+T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons

2019 ◽  
Vol 116 (6) ◽  
pp. 2312-2317 ◽  
Author(s):  
Emmanuelle Coque ◽  
Céline Salsac ◽  
Gabriel Espinosa-Carrasco ◽  
Béla Varga ◽  
Nicolas Degauque ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Interaction Strength ◽  
Adaptive Immune Response ◽  
Clonal Diversity ◽  
Mhc I ◽  
Mutant Sod1 ◽  
Cytotoxicity Activity

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4+T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8+T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8+T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8+T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1)G93Amutant decreased spinal motoneuron loss. Using motoneuron-CD8+T cell coculture systems, we found that mutant SOD1-expressing CD8+T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron andSOD1G93ACD8+T cells. Activated mutant SOD1 CD8+T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8+T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.

scholarly journals Selective expression of H-2 (i-region) loci controlling determinants on helper and suppressor T lymphocytes.

1976 ◽  
Vol 144 (3) ◽  
pp. 685-698 ◽  
Author(s):  
K Okumura ◽  
L A Herzenberg ◽  
D B Murphy ◽  
H O McDevitt ◽  
L A Herzenberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Lymphoid Cells ◽  
Control Surface ◽  
Cell Subpopulation ◽  
Selective Expression ◽  
Suppressor T Lymphocytes ◽  
Cell Subpopulations ◽  
T Cell Subpopulations

Data presented here show that locidentify in the I-region of the H-2 gene complex are selectively expressed in different functional T-cell subpopulations. These loci are closely linked (or possibly identical) to loci that control immune responses. They control surface determinants which identify helper and suppressor T lymphocytes. Determinants described here on allotype suppressor T cells (Ts) are found on normal (nonsuppressed) lymphoid cells, but are not found on helper T cells (Th). These determinants are controlled by a locus mapping in the I region of the H-2 complex. In an accompanying publication we show that this locus (Ia-4) marks a new I subregion (I-J) and is expressed only on T cells. Thus Ia-4 determinants idenfity a T-cell subpopulation which includes Ts but not Th. Th also carry identifying surface determinants controlled by loci that map to the H-2 complex, probably within the I region. These determinants are not found on Ts. Data presented also establish that loci in the I region control determinants on Th, but do not conclusively demonstrate that these are the determinants that distinguish Th from Ts. The selective expression of H-2-controlled determinants on Ts and Th suggests that these determinants are directly involved in immunoregulation.

scholarly journals Influenza virus-specific CD4+ T helper type 2 T lymphocytes do not promote recovery from experimental virus infection.

1994 ◽  
Vol 180 (4) ◽  
pp. 1273-1282 ◽  
Author(s):  
M B Graham ◽  
V L Braciale ◽  
T J Braciale
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
Cd4 T Cells ◽  
Primary Role ◽  
T Helper ◽  
Helper Type

T lymphocytes play a primary role in recovery from viral infections and in antiviral immunity. Although viral-specific CD8+ and CD4+ T cells have been shown to be able to lyse virally infected targets in vitro and promote recovery from lethal infection in vivo, the role of CD4+ T lymphocytes and their mechanism(s) of action in viral immunity are not well understood. The ability to further dissect the role that CD4+ T cells play in the immune response to a number of pathogens has been greatly enhanced by evidence for more extensive heterogeneity among the CD4+ T lymphocytes. To further examine the role of CD4+ T cells in the immune response to influenza infection, we have generated influenza virus-specific CD4+ T cell clones from influenza-primed BALB/c mice with differential cytokine secretion profiles that are defined as T helper type 1 (Th1) clones by the production of interleukin 2 (IL-2) and interferon gamma (IFN-gamma), or as Th2 clones by the production of IL-4, IL-5, and IL-10. Our studies have revealed that Th1 clones are cytolytic in vitro and protective against lethal challenge with virus in vivo, whereas Th2 clones are noncytolytic and not protective. Upon further evaluation of these clonal populations we have shown that not only are the Th2 clones nonprotective, but that pulmonary pathology is exacerbated as compared with control mice as evidenced by delayed viral clearance and massive pulmonary eosinophilia. These data suggest that virus-specific CD4+ T cells of the Th2 subset may not play a primary role in virus clearance and recovery and may lead to immune mediated potentiation of injury.

Development of Effective Immunotherapy for B-Cell Non-Hodgkin’s Lymphoma with CD19-Specific Cytotoxic T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3277-3277
Author(s):  
Keichiro Mihara ◽  
Kazuyoshi Yanagihara ◽  
Chihaya Imai ◽  
Akiro Kimura ◽  
Dario Campana
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Cell Killing ◽  
Hodgkin's Lymphoma ◽  
Single Chain ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Less than 60% of patients with B-cell non-Hodgkin’s lymphoma (B-NHL) can be cured with contemporary therapy. Using artificial receptors it is possible to redirect the specificity of immune cells to tumor-associated antigens, a strategy that holds great potential as a novel cancer therapy. Since B-NHL cells invariably express CD19, we transduced human peripheral blood T lymphocytes with a recently developed receptor (anti-CD19-BB-ζ), which consists of the single-chain variable domain (scFv) of an anti-CD19 monoclonal antibody, the hinge and transmembrane domains of CD8α, and the signaling domains of CD3ζ and 4-1BB. CD3ζ delivers the primary stimulus upon receptor engagement, while 4-1BB delivers co-stimulatory signals that are crucial for T-cell cytotoxicity. It has been shown that elicitation of 4-1BB signaling enhances the immune response to tumors in vivo, even when an immune response cannot be induced by CD28 stimulation. Retroviral transduction led to anti-CD19-BB-ζ expression in T cells with high efficiency: median percent of transduced cells was 60.3% (range, 25.7%–83.4%; n = 9). T lymphocytes expressing anti-CD19-BB-ζ expanded more vigorously that T cells transduced with receptors lacking 4-1BB and exerted powerful cytotoxicity against the CD19+ B-NHL cell lines Raji, Daudi, RL, and HT in vitro: at a 0.5: 1 effector: target ratio, mean (± SD) cell specific lymphoma cell killing was 96.6% ± 4.6% after 5–7 days of culture (4 experiments in each cell line). Transduced T cells were also effective against freshly isolated cells from patients with diffuse large, follicular large, Burkitt, and mantle cell lymphoma cultured on bone marrow-derived mesenchymal cells: in 10 samples, cell killing was 93.6% ± 5.7% at a 0.5: 1 ratio after 5–7 days of culture. Sensitivity to anti-CD19-BB-ζ-mediated killing was observed regardless of high Bcl-2 expression. T cells expressing anti-CD19-BB-ζ were also effective in a xenograft model of NHL, in which NOD/SCID mice were inoculated subcutaneously with lymphoma cells (1 x 107). Subsequent inoculation of T cells (2 x 106) transduced with anti-CD19-BB-ζ receptors significantly suppressed tumor growth, whereas inoculation of T cells transduced with empty control vector had no effect (3 mice for each treatment). These results provide a rationale for clinical testing of autologous T cells modified with anti-CD19-BB-ζ receptors in patients with aggressive or relapsed B-NHLs refractory to conventional therapy.

Analysis of Memory T Lymphocytes Activity Following Stimulation with HLA-A24, A1 and Cw4 Restricted 9- and 10-mer Cytomegalovirus pp65 Overlapping Peptides.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2876-2876
Author(s):  
Monica Ghei ◽  
David F. Stroncek ◽  
Maurizio Provenzano
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Lymphocytes ◽  
Immune Therapy ◽  
Hla Class I ◽  
Class I ◽  
Specific Ctls ◽  
Over Time

Abstract In healthy subjects, primary infection with Cytomegalovirus (CMV) is usually mild or asymptomatic and is effectively controlled by the cell-mediated immune response. However, in immune compromised individuals, such as those with AIDS or after bone marrow transplantation, CMV reactivation is associated with significant morbidity until the individual’s immune system is completely reconstituted. One means of preventing post-transplant CMV infection is adoptive immunotherapy using CMV-specific cytotoxic T cells (CTLs) from the transplant donor. Several 9- and 10-mer HLA class I restricted peptides derived from the immune dominant CMV 65 kd matrix phosphoprotein (pp65) have been shown to produce CMV-specific CTLs. Two overlapping HLA-A24 restricted peptides have been specifically described: pp65 341–349 and pp65 341–350. These are 9- and 10-mer peptides that overlap except for the last amino acid phenylalanine (F) at the C-terminus [QYDPVAALF(F)]. Despite their similarity, the ability of these peptides to induce a T cell response has been reported to differ. Although it has been generally accepted that a unique CMV peptide is bound and presented by each separate HLA class I molecule, recent studies suggest that certain peptides are more promiscuous and may be presented by more than one HLA Class I antigen. For example, the 9-mer pp65 341–349 has been shown to stimulate CTLs from both HLA-A24 and Cw4 donors, while the 10-mer pp65 341–350 has been shown to be reactive with both HLA-A24 and A1 donors. The current investigation sought to compare the potency of these two peptides and determine the optimum peptide size for effective CMV adoptive immune therapy. Both peptides were tested for their ability to stimulate CMV-specific CTLs in HLA-A24, HLA-A1, and HLA-Cw4 restriction. In addition, a pp65 16-mer that included the 9- and 10-mers was tested for its ability to reactivate either CD8+ or CD4+ memory T cells. IFN-γ mRNA transcript as well as protein production were measured by in vitro cell culture assays. Peptide stimulations were performed on isolated CD8 and CD4 T lymphocytes by inducing the cells for 3 hours after a 2-week in vitro sensitization. The goal of the investigation was to determine whether both the 9- and the 10-mer peptides maintained high levels of CTL stimulation over time for all HLA restrictions studied. Moreover, it was important to investigate whether stimulation with the 16-mer, followed by restimulation by the two smaller peptides embedded within the larger sequence, led to effective T cell memory immune response. The 9- and 10-mer peptides effectively stimulated CTLs from HLA-A24, HLA-A1, and HLA-Cw4 CMV seropositive donors. Although both 9- and 10-mer were able to maintain high levels of stimulation over time for all restrictions, the 9-mer induced highest responses in cells expressing HLA-A24 (S.I. 4.07–528) or HLA-Cw4 (S.I. 4.15–483) while the 10-mer induced highest responses in cells expressing HLA-A24 (S.I. 3.5–528) or HLA-A1 (S.I. 8.25–615). The 16-mer peptide was also able to stimulate T cells from all HLA-A24, A1 and Cw4 donors (S.I. 6.95, 4.96, 5.02) at levels that are well maintained over time. This data confirmed that both the 9- and the 10-mer peptides are promiscuous and not restricted to a single HLA antigen. These peptides that have the ability to produce CMV-specific CTLs in patients with several different HLA types present a practical advantage over peptides that are restricted only to a single HLA type, and thus are optimal for CMV adoptive immune therapy.

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