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At least 163 records · Page 9Linked to original sources
PubMed1999

Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibody-dependent cellular cytotoxicity against LFA-3 and HER2/neu.

Treatment of advanced breast cancer with autologous stem cell transplantation is limited by a high probability of disease relapse. In clinical trials, interleukin 2 (IL-2) alone can expand natural killer (NK) cells in vivo and increase their cytotoxic activity against breast cancer cell lines, but this increase is modest. Understanding the mechanisms that mediate NK cell lysis of breast cancer targets may lead to improvements of current immunotherapy strategies. NK cells from normal donors or patients receiving subcutaneous IL-2 were tested in cytotoxicity assays against five breast cancer cell lines. The role of adhesion molecules and antibodies that interact through Fc receptors on NK cells was explored. NK cell lysis of breast cancer targets is variable and is partially dependent on recognition through ICAM-1 and CD18. While blocking CD2 slightly decreased cytotoxicity, contrary to expectations, an antibody against CD58 (the ligand for CD2), failed to block killing and instead mediated an increased cytotoxicity that correlated with target density of CD58. The CD58 antibody-enhanced killing was dependent not only on FcRgammaIII but also on CD2 and ICAM-1/CD18. To further elucidate the mechanism of this CD58 antibody-dependent cellular cytotoxicity (ADCC), another antibody was tested. Trastuzumab (Herceptin), a humanized antibody against HER2/neu, mediated potent ADCC against all the HER2/neu positive breast cancer targets. Unlike CD58 antibody-mediated ADCC, Herceptin ADCC was minimally affected by blocking antibodies to CD2 or ICAM-1/CD18, which suggests a different mechanism of action. This study shows that multiple mechanisms are involved in NK cell lysis of breast cancer targets, that none of the targets are inherently resistant to killing, and that two distinct mechanisms of ADCC can target immunotherapy to breast cancer cells.

Antibodies↗
PubMed1998

Variant antigenic peptide promotes cytotoxic T lymphocyte adhesion to target cells without cytotoxicity.

Timelapse video microscopy has been used to record the motility and dynamic interactions between an H-2Db-restricted murine cytotoxic T lymphocyte clone (F5) and Db-transfected L929 mouse fibroblasts (LDb) presenting normal or variant antigenic peptides from human influenza nucleoprotein. F5 cells will kill LDb target cells presenting specific antigen (peptide NP68: ASNENMDAM) after "browsing" their surfaces for between 8 min and many hours. Cell death is characterized by abrupt cellular rounding followed by zeiosis (vigorous "boiling" of the cytoplasm and blebbing of the plasma membrane) for 10-20 min, with subsequent cessation of all activity. Departure of cytotoxic T lymphocytes from unkilled target cells is rare, whereas serial killing is sometimes observed. In the absence of antigenic peptide, cytotoxic T lymphocytes browse target cells for much shorter periods, and readily leave to encounter other targets, while never causing target cell death. Two variant antigenic peptides, differing in nonamer position 7 or 8, also act as antigens, albeit with lower efficiency. A third variant peptide NP34 (ASNENMETM), which differs from NP68 in both positions and yet still binds Db, does not stimulate F5 cytotoxicity. Nevertheless, timelapse video analysis shows that NP34 leads to a significant modification of cell behavior, by up-regulating F5-LDb adhesive interactions. These data extend recent studies showing that partial agonists may elicit a subset of the T cell responses associated with full antigen stimulation, by demonstrating that TCR interaction with variant peptide antigens can trigger target cell adhesion and surface exploration without activating the signaling pathway that results in cytotoxicity.

Amino Acid Sequence↗
PubMed1997

Residual cytotoxicity and granzyme K expression in granzyme A-deficient cytotoxic lymphocytes.

Cytotoxic lymphocytes contain granules that have the ability to induce apoptosis in susceptible target cells. The granule contents include perforin, a pore-forming molecule, and several granzymes, including A and B, which are the most abundant serine proteases in these granules. Granzyme B-deficient cytotoxic T lymphocytes (CTL) have a severe defect in their ability to rapidly induce apoptosis in their targets, but have an intact late cytotoxicity pathway that is in part perforin-dependent. In this report, we have created mice that are deficient for granzyme A and characterized their phenotype. These mice have normal growth and development and normal lymphocyte development, activation, and proliferation. Granzyme A-deficient CTL have a small but reproducible defect in their ability to induce 51Cr and 125I-UdR release from susceptible allogeneic target cells. Since other granzyme A-like tryptases could potentially account for the residual cytotoxicity in granzyme A-deficient CTL, we cloned the murine granzyme K gene, which is linked to granzyme A in humans, and proved that it is also tightly linked with murine granzyme A. The murine granzyme K gene (which encodes a tryptase similar to granzyme A) is expressed at much lower levels than granzyme A in CTL and LAK cells, but its expression is unaltered in granzyme A-/- mice. The minimal cytotoxic defect in granzyme A-/- CTL could be due to the existence of an intact, functional early killing pathway (granzyme B dependent), or to the persistent expression of additional granzyme tryptases like granzyme K.

Amino Acid Sequence↗
PubMed2005

Fluorescent antigen-transfected target cell cytotoxic T lymphocyte assay for ex vivo detection of antigen-specific cell-mediated cytotoxicity.

Ex vivo detection of virus-specific cytotoxic T lymphocyte (CTL) responses is limited to the use of methods assessing cytokine production, degranulation, or perforin contents of antigen-specific CD8+ T cells. Generally, their cytotoxic activity is detectable only after cultivation. We describe the fluorescent antigentransfected target cellCTL (FATT-CTL) assay, which measures antigen-specific cytotoxicity ex vivo. Target cells were generated by nucleofection with DNA vectors encoding antigengreen fluorescent protein (GFP) fusion proteins. After coculture at various effector : target (E : T) cell ratios, viable and dead GFP-positive cells were quantified by flow cytometry, and antigen-specific target-cell elimination was calculated. The assay was validated with human immunodeficiency virus (HIV) and influenza virusspecific CTL clones and revealed cytotoxicity at lower E : T cell ratios than standard 51Cr-release assays. Moreover, antigen-specific cytotoxicity was detected ex vivo within 1 day in peripheral blood mononuclear cells from HIV-infected individuals. The FATT-CTL assay provides a versatile tool that will advance our understanding of cell-mediated immunity.

Amino Acid Sequence↗
PubMed1996

Interleukin-12 administered in vivo decreases human NK cell cytotoxicity and antibody-dependent cellular cytotoxicity to human immunodeficiency virus-infected cells.

Persons infected with human immunodeficiency virus (HIV) have cellular cytotoxicity defects. Interleukin (IL)-12 is a potent stimulator of cytotoxicity. Fifteen HIV-infected patients were studied in a phase 1, single-dose escalation trial of human recombinant IL-12. One day after subjects received an IL-12 dose of 300 or 1000 ng/kg, they had a reduction in absolute lymphocyte count and peripheral blood mononuclear cell recovery. In evaluable patients 24 h after IL-12 administration, there was a 31% reduction overall in NK cell cytotoxicity (NKC) to HIV-infected cells at all doses and a 52% reduction in antibody-dependent cellular cytotoxicity (ADCC) at doses of 300 and 1000 ng/kg. In vitro incubation of patients' cells with IL-12 (before IL-12 administration) for 24 h increased NKC but had no effect on ADCC. The paradoxic acute reduction in cell number and cytotoxicity in vivo may be due to NK cell trafficking or regulatory cytokine mechanisms not apparent in vitro.

Adolescent↗
PubMed2001

The non-classical MHC class I molecule Qa-1(b) inhibits classical MHC class I-restricted cytotoxicity of cytotoxic T lymphocytes.

The CD94/NKG2A heterodimer is an inhibitory receptor expressed on a subset of mouse NK cells. CD94/NKG2A recognizes the non-classical MHC class I (class Ib) molecule Qa-1(b) and inhibits NK cytotoxicity. Qa-1(b) presents a peptide derived from the leader sequence of classical MHC class I molecules. Here, we examined the role of CD94/NKG2A in T cell-mediated cytotoxicity. Soluble tetrameric Qa-1(b) bound to almost all CD8(+), but not CD4(+), T cells. This binding seems to be mediated by CD8, because COS cells transfected with CD8 also bound Qa-1(b) tetramer. Therefore, the expression of CD94/NKG2 in T cells was further examined by single-cell RT-PCR. Most murine CD8(+) T cells constitutively expressed CD94 and NKG2A transcripts, whereas they were not detected in CD4(+) T cells. Co-expression of Qa-1(b) and D(k) on target cells significantly inhibited cytotoxicity of D(k)-specific cytotoxic T lymphocytes generated by mixed lymphocyte reaction, indicating that Qa-1(b) on antigen-presenting cells interacts with CD94/NKG2A on CD8 T cells and regulates classical MHC class I-restricted cytotoxic T cells. These results suggest a significant role of CD94/NKG2A as an inhibitory receptor on CD8(+) T cells.

Animals↗
PubMed1995

Inhibition of cytotoxicity and cytokine release of CD8+ HIV-specific cytotoxic T lymphocytes by pentoxifylline.

HIV-specific cytotoxic T lymphocytes (CTLs) are an important component of the host immune response against HIV infection, and these cells release a variety of cytokines when they meet their target antigen. Since the phosphodiesterase inhibitor pentoxifylline is being used as a therapeutic agent in clinical trials of HIV infection due to its inhibitory effect on virus replication in vitro, we examined the effect of pentoxifylline on cytotoxicity and cytokine secretion by HIV-specific CD8+ CTLs. Pentoxifylline inhibited cytotoxicity of CTLs and suppressed interferon-gamma, tumor necrosis factor-alpha, and granulocyte-macrophage colony-stimulating factor release by these cells at the transcription level. Suppression of cytokine release resulted in reduced capacity of the CTLs to induce HLA class I and ICAM-1 expression and to stimulate HIV-1 replication. These results suggest that inhibition of HIV-specific CD8+ CTLs by pentoxifylline may be therapeutically relevant. Moreover, this study extends previous observations by demonstrating that, in addition to its ability to suppress cytokine production by macrophages and CD4+ T helper cells, pentoxifylline may inhibit cytotoxicity and cytokine secretion by antigen-specific CD8+ cytotoxic T lymphocytes.

Amino Acid Sequence↗
PubMed2003

CD8-interaction mutant HLA-Cw3 molecules protect porcine cells from human natural killer cell-mediated antibody-dependent cellular cytotoxicity without stimulating cytotoxic T lymphocytes.

BACKGROUND: CD56+ human natural killer (NK) cells are the principal anti-pig cytotoxic effectors in vitro. Expression of certain human leukocyte antigen (HLA) class I molecules in porcine cells can inhibit NK cell-mediated natural cytotoxicity in serum-free medium, but had not been shown to inhibit antibody-dependent cellular cytotoxicity (ADCC) by CD16+ NK cells in the presence of human xenoreactive immunoglobulin G. Moreover, expression of HLA molecules might amplify the previously weak CD8+ cytotoxic T-lymphocyte (CTL) response against porcine cells. METHODS: A novel porcine B-lymphoblastoid cell line (13271) was stably transfected with HLA-Cw*0304 gene constructs encoding wild-type (wt) Cw3 or genetically modified Cw3 unable to interact with CD8 (Cw3-D227K). The Cw3 transfectants were used in limiting dilution assays to estimate the CTL precursor frequency in CD56-depleted human peripheral blood mononuclear cells (PBMC) obtained from eight unrelated donors. The 13271 transfectants were also used as targets for clonal and polyclonal NK cells in the presence and absence of human serum, to measure inhibition of ADCC. RESULTS: Expression of Cw3-wt in 13271 cells significantly increased the human CTL response compared with the empty-vector control transfectant, whereas no significant increase resulted from expression of CD8-interaction mutant Cw3-D227K molecules. The Cw3-D227K mutant was indistinguishable from Cw3-wt in its ability to inhibit both natural cytotoxicity and ADCC mediated by human NK clones that have the appropriate CD158b inhibitory receptor. CONCLUSIONS: Transgenic expression of HLA molecules in pig cells will likely amplify the CD8+ CTL response against the xenograft. Disruption of HLA-CD8 interaction could minimize this amplification without compromising NK-cell inhibition.

Animals↗
PubMed1980

Cytotoxic lymphocytes and antibody-dependent complement-mediated cytotoxicity induced by administration of influenza vaccine.

Recently defined aspects of cellular and humoral antiviral immunity were evaluated in 10 young adults given influenza vaccines containing A/USSR/77 (H1N1) antigens. Cytotoxic lymphocytes were measured by using cryopreserved lymphocytes as effector cells and syngeneic, virus-infected lymphocytes as target cells. An assay previously developed in this laboratory was adapted for the measurement of antibody-dependent, complement-mediated cytotoxicity. Antiviral cytotoxic lymphocyte responses were detected in 5 of 10 volunteers between 3 and 10 days after the initial vaccination. These responses were found both in individuals who were previously primed and in individuals who were not primed to influenza A/USSR/77 antigens. The complement-mediated lysis assay was found to be more sensitive than the hemagglutination inhibition test and probably detected antibodies to both subtype-specific and cross-reactive antigenic determinants. These responses to influenza antigens are similar to those obtained in studies of murine influenza which indicate that cytotoxic lymphocytes and antibody-dependent, complement-mediated cytotoxicity have a role in the early response to acute infection.

Adult↗
PubMed1986

Complement receptors (CR) and cytotoxic responses: monoclonal antibodies directed against CR1 and CR3 inhibit the generation of human allospecific and virus specific cytotoxic cells in vitro.

A variety of cellular immune responses involve complement factors which bind to specific receptors, and modulate or effect a specific reaction. Monoclonal antibodies (MAb) have been generated against complement receptors (CR) 1 and 3, which were utilized to investigate human allogeneic and Epstein-Barr virus specific cytotoxic cells in vitro. MAb OKM1, which binds to the C3bi CR (CR3), and MAb M710, which binds to the C3b/4b CR (CR1), inhibited the generation of both allogeneic and virus specific cytotoxic responses in vitro in a dose-dependent way; doses of 1 microgram/ml (or greater) completely abrogated the cytotoxic responses. Inhibition of these responses was observed when the MAb was added to the cultures at any time point except the last two days. In addition, treatment of the responder (but not the stimulator cells) with either MAb resulted in complete inhibition of cytotoxic responses. These experiment indicate that complement receptors participate in the generation of human cytotoxic responses in vitro.

Antibodies, Monoclonal↗
PubMed1992

Differences between ATP-mediated cytotoxicity and cell-mediated cytotoxicity.

There has been considerable recent interest in the possible role of extracellular ATP in cell-mediated cytotoxicity. To investigate the similarities and differences between ATP-mediated lysis and CTL-mediated lysis, we studied in detail the ATP-mediated lysis of EL-4 cells, which are highly susceptible to lysis by extracellular ATP. ATP-mediated lysis was time and concentration dependent; most lysis occurred within 4 to 6 h of incubation. The kinetics of ATP- and cell-mediated lysis were similar. However, in contrast to CTL-mediated lysis, ATP-mediated lysis of EL-4 cells did not appear to be accompanied by characteristic chromosomal degradation (apoptosis). In order to compare these cytotoxic processes in greater detail, ATP-resistant clones were derived by growing EL-4 cells continuously in the presence of high concentrations of ATP. These cloned EL-4 lines showed marked resistance to ATP-mediated cytotoxicity across a wide range of concentrations but were as susceptible as the parent EL-4 cells to cell-mediated cytotoxicity by an alloreactive effector population from a MLC. Thus, there appear to be a number of differences between ATP-mediated and cell-mediated cytotoxicity in this system; most notable is the identification of cell lines that are resistant to ATP but susceptible to CTL-mediated lysis.

Adenosine Triphosphate↗
PubMedDate not supplied

LAK-cell-mediated cytotoxicity against tumor cell targets used to monitor the stimulatory effect of interleukin-2: cytotoxicity, target recognition and phenotype of effector cells lysing the Daudi, T24 and K562 tumor cell lines.

The T24 transitional bladder carcinoma cell line, the Daudi Burkitt lymphoma cell line and the K562 erythroleukemia cell line have all been used as target cells in 51Cr release assays to measure the in vivo induced lymphokine-activated killer (LAK) cell cytotoxicity during interleukin-2 (IL-2) therapy of cancer patients. However, different relationships between the clinical response to IL-2 treatment and the LAK cytotoxicity have been reported using these three different target cells. The purpose of the present study was to evaluate whether the LAK cytotoxicities measured against these target cells represent similar effector-to-target-cell interactions, so similar conclusions may be drawn of 51Cr release assay results in which the cell lines are used as target cells. The cytotoxicity of peripheral blood mononuclear cells (PBMC) and PBMC depleted of different natural killer and T cell subsets was measured against the three targets. LAK cell recognition of targets was evaluated by cold target inhibition experiments, and the development of LAK-cell-mediated lysis with time was evaluated in 51Cr release assays of varying duration. This study shows that LAK-mediated lysis of T24 and Daudi cells was closely related and LAK cytotoxicity measured in 51Cr release assays against these two target cells may be measurement of similar effector-to-target cell interactions.

Antigens, CD↗
PubMed1986

Cytotoxic lymphokines produced by cloned human cytotoxic T lymphocytes. II. A novel CTL-produced cytotoxin that is antigenically distinct from tumor necrosis factor and alpha-lymphotoxin.

We have cloned lines of IL 2-dependent human T cells derived from alloantigen, soluble antigen (tetanus toxoid), mitogen, or IL 2-stimulated peripheral blood lymphocytes and characterized their surface marker expression and cytolytic activity. The surface phenotype and cytolytic function was compared with the ability of these T cell clones to release cytotoxic lymphokines in response to mitogenic lectins. The cytotoxins released by these CTL clones were detected on the murine L929 target cells in a 16-hr assay. All of the T cell clones, whether stimulated by HLA alloantigens, tetanus toxoid, or mitogens, exhibited killer cell activity and the capacity to secrete a soluble cytotoxin(s). Specific polyclonal antisera to recombinant human tumor necrosis factor (rTNF) and human alpha-lymphotoxin (alpha LT) were unable to neutralize the cytotoxic activity released by most of these CTL clones. These results indicate that human CTL produce a novel antigenic form(s) of cytotoxin that we have termed CTL-toxin. Supernatants from several CTL clones yielded a cytotoxic activity that was partially neutralized (10 to 40%) by saturating levels of anti-TNF (but not anti-alpha LT) indicating that human CTL may be capable of producing a TNF-like molecule. Only two out of 60 CTL clones studied thus far produced a cytotoxic activity that was partially neutralized by anti-alpha LT (20 to 40%). Collectively, these results suggest that although both the CD4 and the CD8 subpopulations of human cytotoxic T cells may be capable of releasing several types of cytotoxins in response to mitogenic signals, the predominant cytotoxin is distinct from alpha LT and TNF.

Antibodies, Monoclonal↗
PubMed1989

Identification by monoclonal antibody of the tumor antigen of a human autologous breast cancer cell that is involved in cytotoxicity by a cytotoxic T-cell clone.

We have already established a pair of human autologous clones, tumor-specific cytotoxic T-lymphocyte clone TcHMC-1 and tumor target clone HMC-1-8, that were derived from the metastatic pleural effusion of a patient with mammary carcinoma. In this paper, we describe the target antigen that was defined by monoclonal antibody 3A2. This monoclonal antibody selectively inhibited the cytotoxic action of TcHMC-1 against HMC1-8 autologous tumor target cells, but not the cytotoxicity of lymphokine-activated killer and possibly natural killer cells against HMC-1-8 cells. Western blot analysis using the 3A2 monoclonal antibody identified a molecule with an approximate molecular weight of 92,000. This antigen was highly expressed on autologous primary cancer cells of breast carcinoma tissue, but not on the normal mammary gland in the same patient. Moreover, this antigen can be detected on approximately 50% of human allogeneic breast carcinomas, but not on other neoplastic tissues such as gastric and colonic carcinomas except for one out of 10 prostatic carcinomas. Nonneoplastic normal cells did not express this antigen. It was also suggested that the antigen is not murine mammary tumor virus-related products. These data suggest that 3A2-defined antigen could participate in the cytotoxicity by human autologous cytotoxic T-lymphocytes as the target molecule expressed on tumor cells.

Antibodies, Monoclonal↗
PubMed1987

Expression of Leu-19 (NKH-1) antigen on IL 2-dependent cytotoxic and non-cytotoxic T cell lines.

The Leu-19 (NKH-1) antigen is expressed on human peripheral blood NK cells and a subset of peripheral blood cytotoxic T lymphocytes that kill "NK-sensitive" tumor cell targets without major histocompatibility complex restriction. In the present study, we demonstrate that the Leu-19 (NKH-1) antigen is also expressed on most interleukin 2 (IL 2) dependent T cell lines and clones that have been maintained in long term culture. The Leu-19 (NKH-1) antigen expressed on an antigen-specific, class I directed cytotoxic T lymphocyte cell line was an approximately 200,000 to 220,000 dalton protein, similar to Leu-19 (NKH-1) protein expressed on natural killer cells and KG1a, an immature stem cell leukemia cell line. Furthermore, Leu-19 (NKH-1) was expressed on both CD4+ and CD8+ IL 2 dependent T cell clones, and was present on both cytotoxic and non-cytotoxic T cell clones. Thus expression of Leu-19 (NKH-1) antigen on cultured cell lines does not directly correlate with cytotoxic function, antigenic specificity, or cell lineage.

Antibodies, Monoclonal↗
PubMed1977

Direct cytotoxicity against chicken erythrocytes in mice. I. Fundamental nature of T cell-mediated cytotoxicity.

Immune responses were examined after immunization with chicken erythrocytes (CRBC) in mice. Cytotoxicity of spleen cells was assessed by the release of 51Cr from labelled target cells. (1) At early stages (day 4-7) after primary intraperitoneal immunization, direct cytotoxicity of spleen cells was raised efficiently in C57BL/6 and AKR mice, but not in C3H/He, SL and DDD mice. Delayed hypersensitivity and antibody production were raised to almost the same extent in all the strains at such periods. (2) Effector cells in direct cytotoxicity were theta-positive and IgG-positive, and glass-nonadherent and Nylon wool column-adherent. Effector cells in antibody-dependent cell-mediated cytotoxicity in the presence of antibody to CRBC were eliminated by treatment with anti-IgG serum, but not by treatment with anti-theta serum. (3) Cytotoxicity and antibody production were raised efficiently after intraperitoneal or intravenous immunization, but not after footpad immunization. On the other hand, delayed hypersensitivity developed most efficiently after footpad immunization.

Animals↗
PubMed1983

Two distinct mechanisms of cytotoxicity by porcine alveolar macrophages in antibody-dependent and immobilized immune complex-dependent cellular cytotoxicity.

The mechanisms of cytotoxicity by porcine pulmonary alveolar macrophages (PAM) involved in antibody-dependent cellular cytotoxicity (ADCC) and immobilized immune complex-dependent cellular cytotoxicity (IIC-DCC) were investigated. The results indicate that IIC-DCC was inhibited by both catalase and thioglycollate broth whereas these peroxide scavengers had no effect on ADCC in an 18-hr chromium-release assay. Furthermore, it was found that when the PAM and red blood cell targets were cross-linked with PHA, catalase still completely eliminated IIC-DCC and had no effect on ADCC, which suggests that catalase is able to penetrate the lytic site when the effector and targets are cross-linked as in ADCC. The presence of cytochalasin B, which inhibits internalization of immune complexes by PAM and presumably prevents intracellular killing, also had no effect on the differential susceptibility of IIC-DCC and ADCC to catalase. Finally, it is shown that the nonspecific cytotoxicity generated by exposing PAM to immune complexes in suspension in conjunction with cytochalasin B, so that the immune complex-bound Fc receptor (FcR) cannot be internalized, also was susceptible to catalase. These data show that the lytic mechanism involved in the nonspecific cytotoxicity generated by exposing PAM to immobilized immune complexes or immune complexes in suspension in conjunction with cytochalasin B, both of which prevent the internalization of immune complex-bound FcR, is mediated solely by peroxide whereas the lytic mechanism involved in ADCC operates, at least partially, through a peroxide-independent mechanism.

Animals↗
PubMed1980

Generation of effector cells from T cell subsets. II. Lyt 123 T cells contain the precursors for all primary cytotoxic effector cells and for cells involved in the regulation of cytotoxic responses.

Mixed responder populations, consisting of selected Lyt-2,3+ cells and unselected T cells from two congenic mouse strains differing in their Lyt-2,3 alleles, were used to study the role of Lyt-1,2,3+ cells in the generation of cytotoxic effector cells in vitro. The fact that, under these conditions, all primary alloreactive and H-2-restricted killer cells ar generated from the unselected T cell population and not from the selected Lyt-2,3+ subset is demonstrated. Isolated, unsensitized Lyt-2,3+ cells are able to produce primary alloreactive cytotoxic T lymphocytes (CTL) when incubated with alloantigen alone, but appear to be suppressed in the pesence of Lyt-1,2,3+ cells. In contrast, mixtures of Lyt-2,3+ cells selected from C57BL/6 T cells previously primed to alloantigen in vitro, and unselected T cells from the Lyt-2,3-congenic partner after exposure to the same antigen give rise to cytotoxic effector cells which derive mainly from the primed Lyt-2,3+ cell pool and not from the unselected T cell population. Both populations were able to generate CTL when sensitized separately with the alloantigen. The data suggest that Lyt-1,2,3+ cells contain all primary precursors for both H-2 restricted and alloreactive killer cells, as well as lymphocytes suppressing the formation of cytotoxic effector cells from unsensitized Lyt-2,3+ cells. The Lyt-2,3+ cell pool most likely contains the secondary CTL precursors. In addition, the same antigen-primed Lyt-2,3+ pool contains suppressor cells which inhibit the formation of primary CTL from Lyt-1,2,3+ cells. The data are discussed with respect to the regulation of cytotoxic responses.

Animals↗