REGULATION OF INTERLEUKIN-2 (IL-2) PRODUCTION BY ENDOTHELIAL CELL (EC) DERIVED SUBSTANCES

1987 ◽  
Author(s):  
J M Teitel ◽  
A Shore ◽  
J McBarron
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Protein A ◽  
Interleukin 2 ◽  
Calcium Ionophore ◽  
Accessory Cell ◽  
Staphylococcal Protein A ◽  
Human Tonsil ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

We recently reported that vascular EC support the staphylococcal protein A (SPA)-induced production of IL-2 by T cells, and furthermore do so synergistically with monocytes. We have now assessed the contributions of EC membrane-associated and secreted factors to these functions. IL-2 was measured by either human tonsil blast of CTLL cell assay. Separation of EC from T cells by a permeable membrane (.45μ pore size) prevented IL-2 production. Consistent with this, supernatant from resting EC (ECs) was also unable to induce IL-2 generation. In addition, neither a crude EC plasma membrane preparation nor paraformaldehyde-fixed EC supported IL-2 production. The combination of fixed EC + ECs likewise did not reconstitute the accessory cell role of intact EC. This was not due to the absence of class II MHC antigens, since EC which were fixed after incubation with interferon (to induce HLA-DR expression) were also unable to promote IL-2. However, the addition of ECs to cultures of T + live EC enhanced IL-2 production by 42% (mean, n=7). This effect did not require the presence of detectable IL-1 in the ECs, and was not reproduced by purified IL-1. When added to unfractionated peripheral blood mononuclear cells (PBM), both fixed EC and ECs enhanced IL-2 production (increments of 120 ± 37% and 115 ± 44% respectively). This effect was dose related, and peaked at 20% ECs by volume. Incubation of EC with calcium ionophore (10™6 M) yielded a supernatant (ECs-i) with greatly enhanced IL-2 promoting activity despite the fact that ionophore alone suppressed IL-2: lllu for T + EC + ECs-i vs. 7u for T + EC + ECs + ionophore. Therefore, substances secreted by EC and presented on the EC surface are able to augment mitogen induced IL-2 production by T cells in the presence of accessory cells. The EC-derived mediator is apparently distinct from IL-1. EC may function in concert with monocytes as important immune regulatory cells at the blood/tissue interface.

Class I–unrestricted noncytotoxic anti–HTLV-I activity of CD8+ T cells

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1994-1995 ◽  
Author(s):  
Masako Moriuchi ◽  
Hiroyuki Moriuchi
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Membrane Filter ◽  
Cd8 T Cell ◽  
Class I ◽  
Type I ◽  
Peripheral Blood Mononuclear ◽  
Permeable Membrane

Abstract Although it is widely believed that viral clearance is mediated principally by the destruction of infected cells by cytotoxic T cells, noncytolytic antiviral activity of CD8+ T cells may play a role in preventing the progression to disease in infections with immunodeficiency viruses and hepatitis B virus. We demonstrate here that (1) replication of human T-lymphotropic virus type I (HTLV-I) is more readily detected from CD8+ T-cell–depleted (CD8−) peripheral blood mononuclear cells (PBMCs) of healthy HTLV-I carriers than from unfractionated PBMCs, (2) cocultures of CD8− PBMCs with autologous or allogeneic CD8+ T cells suppressed HTLV-I replication, and (3) CD8+ T-cell anti-HTLV-I activity is not abrogated intrans-well cultures in which CD8+ cells are separated from CD8− PBMCs by a permeable membrane filter. These results suggest that class I-unrestricted noncytolytic anti–HTLV-I activity is mediated, at least in part by a soluble factor(s), and may play a role in the pathogenesis of HTLV-I infection.

scholarly journals Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex [see comments]

Blood ◽  
1991 ◽  
Vol 78 (7) ◽  
pp. 1770-1780 ◽  
Author(s):  
M Massaia ◽  
A Bianchi ◽  
C Attisano ◽  
S Peola ◽  
V Redoglia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Normal Subjects ◽  
Cross Linking ◽  
Peripheral Blood Mononuclear ◽  
Hla Dr ◽  
Lower Ratio

Abstract Cellular immunity was investigated in 43 patients with multiple myeloma (MM) by assessing 3HTdR uptake induced by monocyte-dependent [CD3 monoclonal antibodies (MoAbs), phytohemagglutinin (PHA)] and monocyte- independent (CD2 MoAbs, ionomycin + phorbolester) stimulations. The former were evaluated in peripheral blood mononuclear cells (PBMNC) and purified T cells; the latter were evaluated in purified T-cell preparations only. MM showed significantly lower PBMNC responses to PHA (P less than .001), soluble OKT3 (CD3) (P = .01), and immobilized OKT3 MoAbs (P = .01). On purification of T cells, MM responses were still defective to soluble T11(2) + T11(3) (CD2) MoAbs (P = .004), phorbol myristate acetate (PMA) plus ionomycin (P less than .001), but significantly higher to plastic-immobilized OKT3 (P = .004). In some MM, 3HTdR uptake, interleukin-2 (IL-2) receptor (CD25) expression, and IL-2 production were as high on stimulation with plastic-immobilized OKT3 as that observed in normal subjects under optimal conditions (ie, plastic-immobilized OKT3 plus accessory signals). CD3 hyperreactivity correlated with the number of CD8+ HLA-DR+ cells in MM T-cell preparations. MM patients with more than 10% CD8+ HLA-DR+ cells had significantly higher responses to immobilized OKT3 (P less than .001), but lower responses to T11(2) plus T11(3) (P = .01), and PMA plus ionomycin (P = .03) than patients with less than 10% CD8+ HLA-DR+ cells. Phenotyping of CD45RA (naive) and CD45R0 (memory) expressions in resting MM T cells showed a lower ratio of CD45RA to CD45R0 in both CD4 (P less than .05) and CD8 (P less than .001) subpopulations. These data indicate that (a) some MM T cells require significantly fewer accessory signals (if any) to express the IL-2 receptor fully, secrete IL-2, and proliferate on multivalent cross-linking of the CD3/TCR complex; and (b) this peculiar state of activation is associated with high HLA-DR expression in CD8+ lymphocytes.

scholarly journals Inhibition of CD4 cross-linking-induced lymphocytes apoptosis by vesnarinone as a novel immunomodulating agent: vesnarinone inhibits Fas expression and apoptosis by blocking cytokine secretion

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2361-2368 ◽  
Author(s):  
N Oyaizu ◽  
TW McCloskey ◽  
S Than ◽  
S Pahwa
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Cytokine Secretion ◽  
Tnf Alpha ◽  
Cross Linking ◽  
Apoptosis Induction ◽  
Peripheral Blood Mononuclear ◽  
Cell Surface Molecule ◽  
Ifn Gamma

Evidence is accumulating that T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals show accelerated cell death through apoptosis. We have recently demonstrated that the cross-linking of CD4 molecules (CD4XL) results in death of normal peripheral T cells through apoptosis and imbalanced cytokine secretion (ie, induction of tumor necrosis factor-alpha [TNF-alpha] and interferon-gamma [IFN-gamma] in the absence of interleukin-2 [IL-2] or IL-4 secretion). These upregulated cytokines (TNF-alpha/IFN-gamma) largely contributed to upregulation of the apoptosis-inducing cell surface molecule, Fas (APO- 1/CD95) and apoptosis induction. The present study investigated the effect of vesnarinone as a novel immunomodulating agent on CD4XL- induced T-cell apoptosis. The addition of vesnarinone to peripheral blood mononuclear cells (PBMC) significantly inhibited CD4XL-induced lymphocyte apoptosis. This apoptosis-inhibitory effect of vesnarinone was associated with the blocking of CD4XL-induced TNF-alpha IFN-gamma secretion and of Fas antigen upregulation. However, vesnarinone did not block effects of exogenously supplemented TNF-alpha/IFN-gamma on Fas induction. These data suggest that vesnarinone inhibits CD4XL-induced TNF-alpha/IFN-gamma secretion, thereby blocking subsequent Fas upregulation and apoptosis induction. Given the potent pathogenic role of imbalanced cytokine secretion observed in HIV-infection, an agent such as vesnarinone may be of therapeutic value in slowing disease progression.

scholarly journals Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis

2013 ◽  
Vol 20 (2) ◽  
pp. 156-164 ◽  
Author(s):  
Y Zhang ◽  
M McClellan ◽  
L Efros ◽  
D Shi ◽  
B Bielekova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Activated T Cells ◽  
Peripheral Blood Mononuclear ◽  
Dependent Relationship ◽  
Cell Counts ◽  
Humanized Monoclonal Antibody

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.

scholarly journals Anti-lymphocyte globulin stimulates normal human T cells to proliferate and to release lymphokines in vitro. A study at the clonal level

Blood ◽  
1988 ◽  
Vol 72 (3) ◽  
pp. 956-963
Author(s):  
GC Barbano ◽  
A Schenone ◽  
S Roncella ◽  
R Ghio ◽  
A Corcione ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Interleukin 2 ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Gm Csf ◽  
Recombinant Interleukin 2 ◽  
Macrophage Colony

Abstract Human peripheral blood mononuclear cells (PBMC) were stimulated in vitro with anti-lymphocyte globulin (ALG), and the phenotypic and functional properties of the blasts obtained were investigated. When stained with monoclonal antibodies (MoAbs), all of the blasts were identified as T cells that expressed predominantly the CD4 phenotype (70% of the cells). The remaining blasts were CD8+. These findings demonstrate that ALG stimulates both helper-inducer and cytotoxic- suppressor cells at random since the CD4 to CD8 ratio in the stimulated blasts was the same as in resting PBMC. This ratio is different from that observed in short-term cultures of T cells stimulated with phytohemagglutinin (PHA) under the same conditions (CD4 to CD8 ratio less than 1). ALG-stimulated T cells were cloned by limiting dilution in the presence of recombinant Interleukin-2 (rIL-2). The clones obtained were expanded and maintained in long term cultures with rIL-2. Thirty-two clones were tested for their capacity of producing colony stimulating activity (CSA) or burst promoting activity (BPA). Twenty- eight of them produced CSA and 12 produced BPA. No correlation was found between the surface phenotype and the ability of the clones to produce CSA or BPA (ie, both the CD4+ and CD8+ clones released the cytokines). When 16 of the same clones were tested for II-2 and gamma interferon (gamma IFN) production, 12 were found to be gamma INF and IL- 2 producers. All of the gamma IFN producers also released IL-2, whereas in the single clones no correlation was found with the capacity of releasing BPA and CSA. Supernatants from selected T-cell clones were also tested for hematopoietic growth factor activities in the presence of neutralizing antisera to human granulocyte-macrophage colony stimulating factor (GM-CSF) or to Interleukin-3 (IL-3). It was found that most CSA was attributable to GM-CSF, whereas BPA was mainly related to the presence of IL-3.

scholarly journals Interleukin-2 production and response to interleukin-2 by peripheral blood mononuclear cells from patients after bone marrow transplantation: II. Patients receiving soybean lectin-separated and T cell-depleted bone marrow

Blood ◽  
1987 ◽  
Vol 70 (5) ◽  
pp. 1595-1603 ◽  
Author(s):  
K Welte ◽  
CA Keever ◽  
J Levick ◽  
MA Bonilla ◽  
VJ Merluzzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Abstract The ability of peripheral blood mononuclear cells (PBMC) to produce and respond to interleukin-2 (IL-2) was evaluated in 50 recipients of HLA- identical bone marrow (BM) depleted of mature T cells by soybean agglutination and E rosetting (SBA-E-BM). In contrast to our previous findings in recipients of unfractionated marrow, during weeks 3 to 7 post-SBA-E-BM transplantation (BMT), PBMC from the majority of patients spontaneously released IL-2 into the culture medium. This IL-2 was not produced by Leu-11+ natural killer cells, which were found to be predominant in the circulation at this time, but by T11+, T3+, Ia antigen-bearing T cells. The IL-2 production could be enhanced by coculture with host PBMC frozen before transplant but not by stimulation with mitogenic amounts of OKT3 antibody, thus suggesting an in vivo activation of donor T cells or their precursors by host tissue. Spontaneous IL-2 production was inversely proportional to the number of circulating peripheral blood lymphocytes and ceased after 7 to 8 weeks post-SBA-E-BMT in most of the patients. In patients whose cells had ceased to produce IL-2 spontaneously or never produced this cytokine, neither coculture with host cells nor stimulation with OKT3 antibody thereafter induced IL-2 release through the first year posttransplant. Proliferative responses to exogenous IL-2 after stimulation with OKT3 antibody remained abnormal for up to 6 months post-SBA-E-BMT, unlike the responses of PBMC from recipients of conventional BM, which responded normally by 1 month post-BMT. However, the upregulation of IL- 2 receptor expression by exogenous IL-2 was found to be comparable to normal controls when tested as early as 3 weeks post-SBA-E-BMT. Therefore, the immunologic recovery of proliferative responses to IL-2 and the appearance of cells regulating in vivo activation of T cells appear to be more delayed in patients receiving T cell-depleted BMT. Similar to patients receiving conventional BMT, however, the ability to produce IL-2 after mitogenic stimulation remains depressed for up to 1 year after transplantation.

scholarly journals The systemic influence of recombinant interleukin 2 on the manifestations of lepromatous leprosy.

1991 ◽  
Vol 173 (4) ◽  
pp. 993-1006 ◽  
Author(s):  
G Kaplan ◽  
W J Britton ◽  
G E Hancock ◽  
W J Theuvenet ◽  
K A Smith ◽  
...  
Keyword(s):  
T Cells ◽  
Endothelial Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Body Burden ◽  
Lepromatous Leprosy ◽  
Lymphoid Cells ◽  
Peripheral Blood Mononuclear ◽  
Recombinant Interleukin 2

14 patients with lepromatous leprosy received twice daily injections of 10 micrograms recombinant interleukin 2 (rIL-2), by the intradermal route, in the skin of the back for 8 d (total dose, 160 micrograms). Lymphokine administration was accomplished without drug toxicity, or the development of acute nerve damage. The majority of patients developed nontender axillary lymphadenopathy during the course of treatment. Local injection sites showed progressively larger zones of induration, peaking at 24 h and persisting for many days. Early 12-h reactions were of a macular, erythematous nature and exhibited an increasingly striking diurnal variation. The morning injection sites were three- to fourfold larger in diameter than those placed in the evening (9 am to 9 pm). Systemic manifestations of intradermal rIL-2 administration were noted. Peripheral blood T cells, including CD4+ and CD8+ phenotypes, increased 2-2.5-fold and NK cells increased sixfold. Elevations in [3H]TdR incorporation into peripheral blood mononuclear cells occurred to a variety of mycobacterial antigens, but not to those of Mycobacterium leprae. Within 2 wk, biopsies at sites far removed from the back showed increased infiltration of mononuclear cells in 12 of 14 patients. Immunocytochemistry revealed the presence of newly emigrated CD4+ T cells, monocytes, and dermal CD1+ Langerhans cells. Endothelial cells of small dermal vessels expressed major histocompatibility complex class II determinants on their surface. Transmission electron microscopy of these specimens revealed markedly enlarged endothelial cells with many surface projections extending into the lumen as well as extravasating lymphoid cells. The numbers of acid-fast M. leprae in the peripheral sites were examined by slit smear and in biopsies of matched leprosy lesions taken before and after IL-2 administration. Within 2 mo, slit smears showed a 0.5 log or greater reduction in 12 of 14 patients, with a mean for all patients tested of 0.5 log units. Biopsy specimens showed a 1 log unit or greater reduction in the bacterial index (B.I.) in 6 of 14 patients. Historical controls in this Nepalese population showed a 0.5 log unit reduction after multidrug therapy over a period of 12 mo. Thus, after 8 d of IL-2 injections, a fivefold reduction in B.I. was observed during the first 2 mo of the study. Antibody levels against M. leprae phenolic glycolipid 1 (PGL-1) and lipoarabinomanan B were markedly elevated after IL-2 injections, while PGL-1 antigen levels were reduced. We conclude that the administration of rIL-2 has had a significant effect in decreasing the total body burden of M. leprae.(ABSTRACT TRUNCATED AT 400 WORDS)

PRTX-100 Inhibits Platelet Phagocytosis In Vitro.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1081-1081 ◽  
Author(s):  
Chris Yatko ◽  
Christopher Herrem ◽  
Samia Siddiqui ◽  
Victor S. Sloan
Keyword(s):  
Mononuclear Cells ◽  
Therapeutic Option ◽  
Protein A ◽  
Flow Cytometric Analysis ◽  
Human Platelets ◽  
Staphylococcal Protein A ◽  
Human Monocytes ◽  
Peripheral Blood Mononuclear ◽  
Vitro Assay

Abstract Background: In idiopathic thrombocytopenic purpura (ITP), autoantibodies bind to platelets which are then phagocytosed by monocytes/macrophages and removed by the reticuloendothelial system. PRTX-100 (Staphylococcal protein A) is being investigated for the treatment of ITP. Objective: To assess the effect of PRTX-100 on phagocytosis of platelets in an in vitro assay. Methods: Human monocytes were isolated from whole blood peripheral blood mononuclear cells (PBMCs) by adherence and cultured for 6 days in RPMI + 5% human serum. 48 hours prior to phagocytosis assay, PRTX-100 was added at 250, 25, and 2.5ng/ml. Human platelets were labeled with a fluorescent (PerCP) lipophilic dye and opsonized with an antibody to MHC Class I (W632). 2×10−5 monocytes were co-cultured with 2×10−7 labeled platelets for 1 hour at 37 ° C. All conditions were performed in triplicate. After an hour, phycoerythrin (PE) labeled anti-CD61 antibody was added to assess surface bound platelets versus ingested platelets. Phagocytosis was determined by flow cytometric analysis. The monocyte population was gated upon by forward and side scatter properties, then verified by staining with CD14-FITC. Percent phagocytosis was calculated as the fraction of ingested platelets (PerCP +/CD61−) to the total PerCP population (PerCP +/CD61−) + ( PerCP+/CD61+) within the gated monocyte population. Results: PRTX-100 inhibits the phagocytosis of W632 opsonized platelets by human monocytes. Phagocytosis of W632 opsonized platelets was 40%, while phagocytosis in the presence of PRTX-100 at concentrations of 250, 25, and 2.5ng/ml was 18.3%, 23%, and 24.3%, respectively. Phagocytosis at 250ng/ml and 25ng/ml was significantly different from control phagocytosis with p values of 0.014 and 0.001 respectively by Student’s t test. Conclusions: PRTX-100 inhibits the phagocytosis of platelets by monocytes, the effector limb of ITP. Prevention of platelet phagocytosis is an important treatment goal in ITP. PRTX-100 has been shown to be generally safe and well-tolerated in a phase I study in healthy volunteers (J Clin Pharmacol, in press). PRTX -100 is a promising therapeutic option for ITP and deserves further study. Effect of PRTX-100 on In Vitro Phagocytosis of Opsonized Human Platelets Effect of PRTX-100 on In Vitro Phagocytosis of Opsonized Human Platelets

scholarly journals INFLUENCE OF REGULATORY T CELLS ON THE FUNCTIONING OF NATURAL KILLER CELLS DURING CANCER IMMUNOTHERAPY

2012 ◽  
Vol 67 (4) ◽  
pp. 60-64
Author(s):  
I. O. Chikileva ◽  
I. Zh. Shubina ◽  
E. V. Kiselevskii
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Nk Cells ◽  
Cancer Immunotherapy ◽  
Natural Killer ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Foxp3 Expression ◽  
Peripheral Blood Mononuclear ◽  
The Common

One of the common arguments against cancer immunotherapy based on natural killer (NK) cells activated in the presence of interleukin-2 (IL-2) is the probability of the activation of regulatory T cells (Tregs) by IL-2 besides NK cells. Thus, we have monitored numbers of FoxP3+CD4+CD25+ T cells in the samples of healthy volunteers’ peripheral blood mononuclear cells (PBMCs) cultured with or without IL-2. We observed marked increase in the percentages of the CD4+CD25+ T cells in the presence of IL-2. Proportions of Foxp3+CD4+CD25+ T cells feebly increased, remained on the same level or even decreased compared to PBMCs cultured without exogenous IL-2. Based on the absence of FoxP3 expression, most of the CD4+CD25+ T cells purified from IL-2 activated PBMCs were not Tregs, but activated Th cells. Moreover, the addition of the purified supposed Tregs to samples of activated NK cells never inhibited their cytotoxic reactions. 

scholarly journals UV irradiation can induce in vitro clonal anergy in alloreactive cytotoxic T lymphocytes

Blood ◽  
1993 ◽  
Vol 82 (1) ◽  
pp. 176-181 ◽  
Author(s):  
T Kobata ◽  
H Ikeda ◽  
Y Ohnishi ◽  
N Urushibara ◽  
TA Takahashi ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Mononuclear Cells ◽  
Interleukin 2 ◽  
Calcium Ionophore ◽  
Target Cells ◽  
Ionophore A23187 ◽  
Peripheral Blood Mononuclear ◽  
High Affinity ◽  
Clonal Anergy

The alloreactive cytotoxic T lymphocytes (CTL) were generated by coculturing peripheral blood mononuclear cells (PBMC) with allogeneic Sa cells (an Epstein-Barr virus [EBV]-transformed B-cell line). The CTL did not proliferate in response to UV-B-irradiated Sa cells unless exogenous interleukin-2 (IL-2) was present, although they could kill the UV-B-irradiated Sa cells. The results indicate that UV-B-irradiated Sa cells do not provide sufficient signals for the proliferation of the CTL while they can be recognized by CTL and induce high-affinity IL-2 receptor (IL-2R) expression on them. The alloreactive CTL could be rendered anergic by previous exposure to UV-B-irradiated Sa cells. The alloreactive CTL previously stimulated with UV-B-irradiated Sa cells failed to proliferate in response to nontreated Sa cells. Proliferation of the anergic CTL could not be restored by Sa cells and exogenous IL-2 but by the combination of phorbol 12-myristate 13-acetate (PMA) and calcium ionophore (A23187). The anergic CTL showed a considerably low cytotoxic activity against Sa target cells. The expression of TCR on the anergic CTL was downregulated while expression of high-affinity IL- 2R was upregulated. Their CD28 and CD8 expression were unchanged. In addition, the proliferative response and cytotoxicity of the anergic CTL to Sa cells could be restored after the cells had been rested for 7 days to allow reexpression of TCR. These results suggest that downregulation of T-cell receptor (TCR) and impairment in the post-IL- 2/IL-2R signaling pathway are relevant to the clonal anergy induced in the alloreactive CTL by stimulation of UV-B-irradiated Sa cells.

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