scholarly journals Interleukin 1 production during accessory cell-dependent mitogenesis of T lymphocytes.

1989 ◽  
Vol 169 (3) ◽  
pp. 1121-1136 ◽  
Author(s):  
N Bhardwaj ◽  
L L Lau ◽  
S M Friedman ◽  
M K Crow ◽  
R M Steinman
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Third Party ◽  
Accessory Cell ◽  
Cell Contact ◽  
T Cell Clones ◽  
Hla Dr ◽  
Cell Clones ◽  
Alloreactive T Cell

We have studied the control and significance of IL-1 production in human leukocyte cultures during accessory cell-dependent, T lymphocyte mitogenesis using sensitive bioassays and immunolabeling techniques. In primary antigen-dependent systems like the MLR, IL-1 production was not detected in accessory cells (monocytes, dendritic cells) or T cells, suggesting that it is not an early product in these responses. However, monocytes could be induced to make IL-1 after interacting with sensitized antigen-specific T cells. Both alloreactive T cell clones or freshly prepared lymphoblasts induced IL-1 provided the monocytes carried the HLA-DR antigens to which the T cells were initially sensitized. Even in these circumstances, dendritic cells and B cells failed to make IL-1. The mechanism whereby activated T cells induce IL-1 in monocytes was explored. Supernatants from cocultures of monocytes and T cells or several recombinant cytokines induced little or no IL-1. A more potent antigen independent pathway of IL-1 induction was identified. IL-1 could be induced in third-party HLA-DR nonspecific monocytes in cocultures of alloreactive T cell clones or blasts and HLA-DR-specific dendritic cells. The induction was factor independent since dendritic cells and T blasts placed in a chamber separate from third-party monocytes by a semipermeable membrane did not induce monocyte IL-1. These results suggest that a cell contact mechanism rather than an IL-1-inducing factor leads to IL-1 production. The role of IL-1 in T cell proliferation was tested with a polyclonal anti-IL-1 antibody. The antibody failed to block the proliferation of primary T cells, or alloreactive T cell clones and blasts stimulated with HLA-specific monocytes or dendritic cells, even though IL-1 in the medium was neutralized.

Epitopic analysis of HLA DR molecule expression on alloreactive T-cell clones

1988 ◽  
Vol 23 (3) ◽  
pp. 207-221 ◽  
Author(s):  
M. Bonneville ◽  
J.F. Moreau ◽  
M.A. Peyrat ◽  
G. Merdrignac ◽  
D.J. Charron ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Clones ◽  
Hla Dr ◽  
Cell Clones ◽  
Alloreactive T Cell

scholarly journals A small number of anti-CD3 molecules on dendritic cells stimulate DNA synthesis in mouse T lymphocytes.

1989 ◽  
Vol 169 (3) ◽  
pp. 1153-1168 ◽  
Author(s):  
N Romani ◽  
K Inaba ◽  
E Puré ◽  
M Crowley ◽  
M Witmer-Pack ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Dna Synthesis ◽  
Specific Antigen ◽  
Accessory Cell ◽  
Binding Studies ◽  
Cell Clones ◽  
Accessory Cells ◽  
Cell Assays

Resting T cells enter cell cycle when challenged with anti-CD3 mAb and accessory cells that bear required Fc receptors (FcR). Presentation of anti-CD3 is thought to be a model for antigens presented by accessory cells to the TCR complex. We have obtained evidence that the number of anti-CD3 molecules that are associated with the accessory cell can be very small. We first noticed that thymic dendritic cells and cultured, but not freshly isolated, epidermal Langerhans cells (LC) were active accessory cells for responses to anti-CD3 mAb. DNA synthesis was abrogated by a mAb to the FcR but not by mAb to other molecules used in clonally specific antigen recognition, i.e., class I and II MHC products or CD4 and CD8. The requisite FcR could be identified on the LC but in small numbers. Freshly isolated LC had 20,000 FcR per cell, while the more active cultured LC had only 2,000 sites, using 125I-anti-FcR mAb in quantitative binding studies. Individual LC had similar levels of FcR, as evidenced with a sensitive FACS. FcR could not be detected on T cells or within the dendritic cell cytoplasm, at the start of or during the mitogenesis response. When the response was assessed at 30 h with single cell assays, at least 20 T cells became lymphoblasts per added LC, and at least 8 T cells were synthesizing DNA while in contact with the LC in discrete cell clusters. To the extent that anti-CD3 represents a polyclonal model for antigen presentation to specific T cell clones, these results suggest two conclusions. First, only 200-300 molecules of ligand on dendritic cells may be required to trigger a T cell. Second, the maturation of LC in culture entails "sensitizing" functions other than ligand presentation (anti-CD3 on FcR) to clonotypic T cell receptors.

Human Alloreactive CD4+ T Cells as Potent Effector Cells and Sole Mediators of Anti-Tumor Responses in a NOD/SCID Mouse Model for Human Acute Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1245-1245 ◽  
Author(s):  
Sanja Stevanovic ◽  
Marieke Griffioen ◽  
Marianke LJ Van Schie ◽  
Roelof Willemze ◽  
J.H. Frederik Falkenburg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Class Ii ◽  
Hla Class Ii ◽  
Cd4 T Cell ◽  
Leukemic Cells ◽  
T Cell Clones ◽  
Hla Dr ◽  
Cell Clones

Abstract Donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation (alloSCT) can be a curative treatment for patients with hematological malignancies. The therapeutic benefit of DLI is attributed to a graft versus leukemia (GvL) reactivity mediated by donor T cells recognizing allo-antigens on malignant cells of the patient. Donor T cells, however, often recognize allo-antigens which are broadly expressed in non-malignant tissues of the patient, thereby causing severe graft versus host disease (GvHD). In contrast to HLA class I molecules which are ubiquitously expressed on all nucleated cells, HLA class II molecules are predominantly expressed on cells of the hematopoietic system, and therefore CD4+ T cells may selectively mediate GvL reactivity without GvHD. Several clinical studies have indeed demonstrated that CD8-depleted DLI after alloSCT can lead to clinical remissions with reduced incidence of GvHD. Since in most of these studies DLI was contaminated with CD8+ T cells, it remained unclear whether CD4+ T cells alone are capable of mediating GvL reactivity. To assess the capacity of purified CD4+ T cells to solely exert GvL reactivity we compared the anti-tumor effects of CD4+ DLI and CD3+ DLI in a NOD/SCID mouse model of human acute leukemia. Iv injection of primary human leukemic cells from three different patients reproducibly resulted in engraftment of leukemia in mice, as monitored by peripheral blood analysis. Three weeks after inoculation of leukemic cells, established tumors were treated by infusion of human donor T cells. In mice treated with CD4+ DLI (5*106 CD4+ T cells), the emergence of activated (HLA-DR+) T cells coincided with rapid disappearance of leukemic cells, showing similar kinetics as for CD3+ DLI (consisting of 5*106 CD4+ T cells and 3*106 CD8+ T cells). To analyze the specific reactivity of T cells responsible for the anti-leukemic effect, we clonally isolated human CD45+ T cells during the anti-tumor response following CD4+ DLI in which the donor was matched for HLA class I and mismatched for the HLA-DR (DRB1*1301), -DQ (DQB1*0603) and –DP (DPB1*0301/0401) alleles of the patient. A total number of 134 CD4+ T cell clones were isolated expressing various different TCR Vbeta chains. Most of the isolated CD4+ T cell clones (84%) were shown to be alloreactive, as determined by differential recognition of patient and donor EBV-transformed B cells (EBV-LCL) in IFN-g ELISA. A substantial number of these CD4+ T cell clones also exerted cytolytic activity (17%), as demonstrated by specific reactivity with patient EBV-LCL but not donor EBV-LCL in a 10 hr 51Cr-release cytotoxicity assay. Further characterization of the specificity of 20 CD4+ T cell clones using blocking studies with HLA class II specific monoclonal antibodies illustrated HLA class II restricted recognition directed against HLA-DR (n=3), HLA-DQ (n=16) and HLA-DP (n=1) molecules of the patient. Of the 127 alloreactive CD4+ T cell clones, only 36 clones directly recognized primary leukemic cells of the patient. Flowcytometric analysis demonstrated that HLA class II, and in particular HLA-DQ, molecules were expressed at relatively low levels on patient leukemic cells as compared to patient EBV-LCL. Upregulation of HLA class II and costimulatory molecules on patient leukemic cells upon differentiation in vitro into leukemic antigen presenting cells (APC) resulted in recognition of patient leukemic cells by all alloreactive CD4+ T cell clones. Therefore, we hypothesize that the alloreactive CD4+ T cells have been induced in vivo by patient leukemic cells, which, upon interaction with T cells or other environmental factors, acquired an APC phenotype. In conclusion, our data show that alloreactive CD4+ T cells can be potent effector cells and sole mediators of strong antitumor responses in a NOD/SCID mouse model for human acute leukemia.

Graft Versus Leukemia Separates From Graft Versus Host Disease By Magnitude and Avidity Of The Allo-Reactive T Cell Response After Allogeneic Stem Cell Transplantation and Donor Lymphocyte Infusion

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2014-2014
Author(s):  
Cornelis A.M. van Bergen ◽  
Simone A.P. Van Luxemburg-Heijs ◽  
Matthijs Eefting ◽  
Maria W. Honders ◽  
Inge Jedema ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Response ◽  
T Cell Response ◽  
Functional Avidity ◽  
T Cell Clones ◽  
Inflammatory Conditions ◽  
Hla Dr ◽  
Cell Clones

Abstract Donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) can be a curative treatment for patients with hematological malignancies due to the capacity of allo-reactive donor derived T cells to mediate a curative potent graft versus leukemia (GVL) effect. However, associated acute graft versus host disease (GVHD) remains a major risk. To study the role of CD8+ T cells in GVL reactivity and GVHD, we selected patients who responded to DLI (without preceding cytoreductive treatment) for recurrent disease or incomplete donor chimerism after alloSCT. The patients were grouped according to absence (7 patients) or presence (6 patients) of GVHD. To quantify the number of circulating activated CD8+ T cells before DLI and at the time of disease regression or conversion to full donor chimerism we measured the frequencies of CD8+ HLA-DR+ T cells in peripheral blood samples by flowcytometry. Before DLI, highly variable numbers of CD8+ HLA-DR+ T cells were found (37.8 ± 42.9 x106/L), that significantly increased after DLI (309±473 x106/L, p<0.005), demonstrating involvement of CD8+ HLA-DR+ T cells in immune responses after DLI. To determine the specificity and functional avidity of the CD8+ HLA-DR+ T cells, these cells were isolated using flowcytometric cell sorting and clonally expanded. From a total of 30 samples, on average 225 T cell clones per sample were obtained and tested for recognition of patient and donor derived EBV-LCL, CD40L stimulated B cells (CD40L-B cells) and monocyte derived dendritic cells (monoDC). Surprisingly, in many samples from both patient cohorts high percentages of clones recognizing EBV-LCL derived from both patient and donor but not recognizing CD40L-B cells and monoDC were found. These T cells may be involved in anti-EBV responses irrespective of the presence of a GVL effect or GVHD. To investigate whether the magnitude of the allo-immune response was different in patients with or without GVHD coinciding the GVL effect, we compared the frequencies of allo-reactive T cell clones in samples from both patient groups. Significantly lower percentages of allo-reactive T cell clones were found in patients without GVHD as compared to patients with GVHD (5.1 ± 7.0% versus 32.5 ± 20.0% respectively, p<0.01), showing that coinciding GVHD is associated with an increased magnitude of the allo-reactive T cell response. Per patient, we determined the number of unique antigens targeted by the isolated T cell clones by characterizing the targeted MiHA using whole genome association scanning. In line with the lower total number of allo-reactive T cells, a lower number of unique MiHA was targeted in patients without GVHD (2.7±3.5) as compared to patients with GVHD (10.2±5.8, p=0.015). To determine whether occurrence of GVHD could be explained by the tissue specificity and functional avidity of the allo-reactive T cell response after DLI, we tested the T cell clones obtained from both patient cohorts for recognition of fibroblasts (FB) derived from skin biopsies of the patient. To mimic pro-inflammatory conditions, FB were pretreated for 4 days with 100 IU/ml IFN-γ. Recognition of untreated FB was exclusively mediated by T cell clones obtained from patients with GVHD, whereas recognition of IFN-γ pretreated FB was found for clones isolated from patients with or without coinciding GVHD. In addition, several T cell clones isolated from patients without GVHD were found to be directed against MiHA encoded by genes with a broad expression profile in non-hematopoietic cells comprising FB, despite absence of FB recognition under non-inflammatory conditions. This suggests that in addition to the tissue expression profile of the MiHA other factors, comprising the local inflammatory milieu, play a role in the risk of developing GVHD. In conclusion, our data show a strong correlation between the magnitude and the functional avidity of the allo-reactive CD8+ T cell response and the occurrence of GVHD after DLI. We hypothesize that the limited production of pro-inflammatory cytokines due to the moderate magnitude of the immune response in patients mounting a GVL response without coinciding GVHD reactivity may have prevented the induction of GVHD by the lower avidity allo-reactive T cells, that under pro inflammatory conditions can mediate GVHD by recognition of normal non-hematopoietic cells of the patient. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Generation of antigen receptor-specific suppressor T cell clones in man.

1986 ◽  
Vol 164 (3) ◽  
pp. 950-955 ◽  
Author(s):  
N Mohagheghpour ◽  
N K Damle ◽  
S Takada ◽  
E G Engleman
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antigen Receptor ◽  
Suppressor Cells ◽  
Suppressive Effect ◽  
T Cell Clones ◽  
Suppressor T Cell ◽  
Hla Dr ◽  
Cell Clones

We have shown previously that CD8+ T cells proliferate upon exposure to autologous, antigen primed CD4+ T cells, and suppress the response of fresh T cells to the priming antigen but not irrelevant antigens. The stimulus and target of suppression in this system appears to be the antigen receptor on the surface of CD4+ cells, rather than the nominal antigen. In the current study, alloantigen primed CD4+ inducer cells and IL-2-containing medium were used to generate clones of suppressor cells from several individuals. The clones inhibited the response of fresh autologous T cells only to the original allogeneic stimulator cell and to stimulator cells that shared HLA-DR antigens with the priming cell. The clones were also genetically restricted, since they inhibited the response of HLA-A,B-compatible but not HLA-A,B-incompatible individuals. The availability of a method for reproducibly generating antigen receptor-specific suppressor T cell clones in vitro should make it possible to clarify the mechanism, whereby such cells are activated and exert their suppressive effect.

scholarly journals Human T cells cannot act as autonomous antigen-presenting cells, but induce tolerance in antigen-specific and alloreactive responder cells.

1992 ◽  
Vol 176 (3) ◽  
pp. 875-880 ◽  
Author(s):  
S Sidhu ◽  
S Deacock ◽  
V Bal ◽  
J R Batchelor ◽  
G Lombardi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Clone ◽  
Antigen Presenting Cells ◽  
Accessory Cell ◽  
T Cell Clones ◽  
Human T Cell ◽  
Cell Clones ◽  
T Cell Clone ◽  
Antigen Presenting

The ability of two HLA-DR-expressing human T cell clones to function as antigen-presenting cells (APC) was investigated using highly purified T cells. The results demonstrated that these T cell clones are unable to act as autonomous APC, and that recognition of nominal or alloantigens on the surface of T cells leads to a state of nonresponsiveness. The first observation was that a T cell clone with specificity for the 306-324 peptide of influenza hemagglutinin (HA), and raised from a DR1 responder, exhibited apparent degeneracy of major histocompatibility complex restriction when cultured with peptide in the presence of peripheral blood mononuclear cells (PBMC) expressing a wide variety of structurally unrelated DR types. However, when the PBMC were pulsed with peptide and washed before coculture with the clone, peptide was exclusively recognized with DR1Dw1. This implied that in the presence of soluble peptide the T cells were displaying ligand to each other, and that the third-party APC were providing costimulatory signals. To test the ability of T cells to act as autonomous APC, accessory cell-free preparations of two DR1-restricted clones were cultured with peptide in the presence or the absence of added B cell APC. T cell purity was established by the absence of proliferation in response to the mitogen phytohemagglutinin (PHA). PHA-nonresponsive T cells were completely unable to proliferate in response to peptide alone; furthermore, preculture of the HA-specific clone, in the complete absence of accessory cells, with the same concentration of peptide (1 microgram/ml) that induced optimal proliferation when presented by conventional APC, led to profound nonresponsiveness. The same phenomenon was also observed when two of three anti-DR1 alloreactive T cell clones were precultured with a DR1-expressing T cell clone. The ability of the DR1-expressing clone to induce nonresponsiveness in anti-DR1 clones correlated with recognition of the DR1 alloantigen on the DR1-expressing clone.

scholarly journals Differential requirements of B cells from normal and allergic subjects for the induction of IgE synthesis by an alloreactive T cell clone.

1985 ◽  
Vol 162 (1) ◽  
pp. 202-214 ◽  
Author(s):  
D T Umetsu ◽  
D Y Leung ◽  
R Siraganian ◽  
H H Jabara ◽  
R S Geha
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Cell Clone ◽  
T Cell Clones ◽  
Igg Synthesis ◽  
Cell Clones ◽  
T Cell Clone ◽  
Ige Synthesis ◽  
Alloreactive T Cell

Human T cell helper/inducer clones were used to induce IgE synthesis in B cells from both allergic and nonallergic donors. An alloreactive T cell clone, activated by recognition of specific HLA-DR antigens, stimulated peripheral blood B cells from both allergic and nonallergic donors to synthesize IgE antibody. B cells of allergic donors differed from those of nonallergic donors in their requirements for induction of IgE synthesis. Induction of IgE synthesis in B cells from nonallergic individuals occurred only under conditions of cognate interaction, in which the B cells expressed the alloantigen recognized by the T cells. In contrast, IgE synthesis in B cells from allergic donors occurred under conditions of cognate interaction with T cells as well as bystander conditions where the B cells did not express the alloantigen recognized by the T cell clones and where the T cell clones were stimulated by third-party monocytes bearing the relevant alloantigens. Furthermore, bystander stimulation of IgE synthesis in allergic donors occurred in the presence of tetanus toxoid (TT) antigen-specific T cell clones activated by the appropriate TT-pulsed monocytes. In contrast to the differing requirements of B cells from normal vs. allergic subjects for the induction of IgE synthesis, these B cells did not differ in their requirements for the induction of IgG synthesis. IgG synthesis was induced in all B cells under conditions of cognate interaction with the T cells as well as under conditions of bystander stimulation. These results suggest that cognate T-B cell interactions may be important in the development of IgE immune responses in the normal host.

Transfer of Diabetes in the NOD-scid Mouse by CD4 T-Cell Clones: Differential Requirement for CD8 T-Cells

Diabetes ◽  
1996 ◽  
Vol 45 (3) ◽  
pp. 328-336 ◽  
Author(s):  
J. D. Peterson ◽  
K. Haskins
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Scid Mouse ◽  
Cd4 T Cell ◽  
T Cell Clones ◽  
Cell Clones
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