scholarly journals Synthetic peptides as antigens and competitors in recognition by H-2-restricted cytolytic T cells specific for HLA.

1988 ◽  
Vol 167 (4) ◽  
pp. 1391-1405 ◽  
Author(s):  
J L Maryanski ◽  
P Pala ◽  
J C Cerottini ◽  
G Corradin
Keyword(s):  
T Cells ◽  
Mhc Class I ◽  
Synthetic Peptide ◽  
Class I ◽  
Target Cells ◽  
Protein Fragments ◽  
Peptide Recognition ◽  
Genes Encoding ◽  
Mouse Cells ◽  
P815 Mouse

The specificity of peptide recognition by a number of Kd-restricted CTL clones specific for HLA-CW3 or HLA-A24 was investigated. The CTL clones were derived from DBA/2 (H-2d) mice immunized with syngeneic P815 mouse cells transfected with genes encoding HLA-CW3 or HLA-A24 class I molecules. We had previously shown that CTL clones that lysed P815-CW3 transfectant target cells could lyse P815 (HLA-) target cells incubated with synthetic CW3 peptides corresponding to the COOH-terminal end of the alpha 2 domain. In the present study, we found that Kd-restricted CTL clones that lysed P815-A24 transfectant target cells recognized a synthetic peptide from the same region (residues 170-182) of the A24 molecule. CW3 and A24 differ by only one amino acid within this region. Recognition of CW3 or A24 peptides corresponded exactly with lysis of P815-HLA transfectants both for clones that mutually exclusively lysed CW3 or A24 transfectant target cells and for CW3/A24 crossreactive CTL clones. The latter CTL clones that lysed both CW3 and A24 transfectant target cells showed a clear preference for the peptide corresponding to the immunizing HLA allele. The homologous CW3 and A24 peptides could compete with each other for recognition, in contrast to a peptide from the same region of HLA-B7. Peptides from the corresponding region of the endogenous Kd and Dd/Ld molecules could also inhibit recognition of CW3 and A24 peptides. Competition with peptides apparently occurred at the level of the target cell. These results are consistent with a model whereby MHC class I molecules position protein fragments or peptides for specific recognition by T cells.

scholarly journals Antigen-specific recognition of autologous leukemia cells and allogeneic class-I MHC antigens by IL-2-activated cytotoxic T cells from a patient with acute T-cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 343-353 ◽  
Author(s):  
P Fisch ◽  
G Weil-Hillman ◽  
M Uppenkamp ◽  
JA Hank ◽  
BP Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Class I ◽  
Target Cells ◽  
Class I Mhc ◽  
Blood Lymphocytes ◽  
Mhc Class I Antigens

Abstract Culturing of leukemic blood lymphocytes from a patient with acute T- cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T- cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine-activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabeled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.

scholarly journals Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles.

1996 ◽  
Vol 184 (2) ◽  
pp. 789-794 ◽  
Author(s):  
A D'Andrea ◽  
C Chang ◽  
J H Phillips ◽  
L L Lanier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cytokine Production ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Target Cells ◽  
T Cell Clone ◽  
Mhc Class I Molecules

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) and T cells that specifically recognize defined groups of polymorphic human histocompatibility leukocyte antigen (HLA) class I molecules. Interactions between KIRs on NK or T cells and major histocompatibility complex (MHC) class I molecules on potential target cells inhibit cell-mediated cytotoxicity, presumably by delivering a negative signal preventing lymphocyte activation. In this study we examined whether KIRs also regulate cytokine production induced in response to T cell receptor-dependent T cell activation. CD4+ and CD8+ T cell clones were stimulated by bacterial superantigens in the presence or absence of monoclonal antibodies (mAbs) against the KIR NKB1 or MHC class I molecules, and production of tumor necrosis factor alpha and interferon gamma was evaluated. When bacterial superantigen was presented by an autologous antigen-presenting cell (APC) to a KIR+ T cell clone, cytokine production was always enhanced in the presence of anti-MHC class I mAb. Similarly, anti-KIR mAb also augmented cytokine production, provided that the APC expressed a HLA class I allele recognized by the KIR. These results suggest that recognition of autologous MHC class I molecules by KIR+ T cells provides a regulatory mechanism acting to modulate the potency of their responses to antigenic challenge.

Characterization of MHC Class-I Restricted TCRαβ+CD4−CD8− Double-Negative T Cells Recognizing the gp100 Antigen from a Melanoma Patient after gp100 Vaccination

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4905-4905
Author(s):  
Simon Voelkl ◽  
Tamson Moore ◽  
Michael Rehli ◽  
Michael Nishimura ◽  
Karin Fischer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Peripheral Blood ◽  
Melanoma Patient ◽  
Cell Clone ◽  
Class I ◽  
Target Cells ◽  
Double Negative ◽  
T Cell Clone

Abstract The immune attack against malignant tumors requires the concerted action of CD8+ cytotoxic T lymphocytes (CTL) as well as CD4+ T helper cells. The contribution of T cell receptor (TCR)αβ+ CD4− CD8− double-negative (DN) T cells to anti-tumor immune responses is widely unknown. In previous studies, we have demonstrated that DN T cells with a broad TCR repertoire are present in humans in the peripheral blood and the lymph nodes of healthy individuals. Here we characterize a human DN T cell clone (T4H2) recognizing an HLA-A2-restricted melanoma-associated antigenic gp100-peptide isolated from the peripheral blood of a melanoma patient. Antigen recognition by the T4H2 DN clone resulted in specific secretion of IFN-γ and TNF. Although lacking the CD8 molecule the gp100-specifc DN T cell clone was able to confer antigen-specific cytotoxicity against gp100-loaded target cells as well as HLA-A2+ gp100 expressing melanoma cells. The cytotoxic capacity was found to be perforin/granzymeB-dependent. Together, these data indicate that functionally active antigen-specific DN T cells recognizing MHC class I-restricted tumor-associated antigen (TAA) may contribute to anti-tumor immunity in vivo.

scholarly journals Lassa Fever Virus Peptides Predicted by Computational Analysis Induce Epitope-Specific Cytotoxic-T-Lymphocyte Responses in HLA-A2.1 Transgenic Mice

2005 ◽  
Vol 12 (10) ◽  
pp. 1223-1230 ◽  
Author(s):  
Agnieszka Boesen ◽  
Krishnan Sundar ◽  
Richard Coico
Keyword(s):  
T Cells ◽  
Transgenic Mice ◽  
Mhc Class I ◽  
Lassa Fever ◽  
Fever Virus ◽  
Class I ◽  
Computer Assisted ◽  
Target Cells ◽  
Lassa Fever Virus ◽  
Hla A2.1

ABSTRACT Lassa fever is a hemorrhagic disease caused by Lassa fever virus (LV). Although the precise host defense mechanism(s) that affords protection against LV is not completely understood, cellular immunity mediated by cytotoxic T lymphocytes (CTLs) plays a pivotal role in controlling viral replication and LV infection. To date, there have been no reports mapping major histocompatibility complex (MHC) class I-binding CTL epitopes for LV. Using computer-assisted algorithms, we identified five HLA-A2.1-binding peptides of LV glycoprotein (GP) and two peptides from LV nucleoprotein (NP). Synthesized peptides were examined for their ability to bind to MHC class I molecules using a flow cytometric assay that measures peptide stabilization of class I. Three of the LV-GP peptides tested (LLGTFTWTL, SLYKGVYEL, and YLISIFLHL) stabilized HLA-A2. The LV-NP peptides tested failed to stabilize this HLA-A2. We then investigated the ability of the HLA-A2-binding LV-GP peptides to generate peptide-specific CTLs in HLA-A2.1 transgenic mice. Functional assays used to confirm CTL activation included gamma interferon enzyme-linked immunospot (ELISPOT) assays and intracellular cytokine staining of CD8+ T cells from peptide-primed mice. CTL assays were also performed to verify the cytolytic activity of peptide-pulsed target cells. Each of the LV-GP peptides induced CTL responses in HLA-A2-transgenic mice. MHC class I tetramers prepared using one LV-GP peptide that showed the highest cytolytic index (LLGTFTWTL) confirmed that peptide-binding CD8+ T cells were present in pooled lymphocytes harvested from peptide-primed mice. These findings provide direct evidence for the existence of LV-derived GP epitopes that may be useful in the development of protective immunogens for this hemorrhagic virus.

scholarly journals Selective deletion of antigen-specific CD8+ T cells by MHC class I tetramers coupled to the type I ribosome-inactivating protein saporin

Blood ◽  
2006 ◽  
Vol 109 (8) ◽  
pp. 3300-3307 ◽  
Author(s):  
Paul R. Hess ◽  
Carie Barnes ◽  
Matthew D. Woolard ◽  
Michael D. L. Johnson ◽  
John M. Cullen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Therapeutic Potential ◽  
Class I ◽  
Target Cells ◽  
Type I ◽  
Ribosome Inactivating Protein ◽  
Cell Immunity

Abstract CD8+ cytotoxic T lymphocytes (CTLs) are important effector cells responsible for tissue destruction in several autoimmune and allograft-related diseases. To discover if pathogenic T cells could be selectively deleted, we investigated the ability of a toxin coupled to major histocompatibility complex (MHC) class I tetramers to kill antigen-specific CD8+ T cells. H2-Db tetramers were assembled using streptavidin conjugated to the ribosome-inactivating protein (RIP) saporin (SAP). These tetramers inhibited ribosome activity in vitro, retained the T-cell receptor (TCR)–binding specificity of their nontoxic counterparts, and were internalized by 100% of target cells, leading to cell death in 72 hours. Cytotoxicity was dependent on the tetramer dose and avidity for the T cell. A single injection of the SAP-coupled tetramer eliminated more than 75% of cognate, but not control, T cells. This work demonstrates the therapeutic potential of cytotoxic tetramers to selectively eradicate pathogenic clonotypes while leaving overall T-cell immunity intact.

scholarly journals Vaccination of rhesus monkeys with synthetic peptide in a fusogenic proteoliposome elicits simian immunodeficiency virus-specific CD8+ cytotoxic T lymphocytes.

1992 ◽  
Vol 176 (6) ◽  
pp. 1739-1744 ◽  
Author(s):  
M D Miller ◽  
S Gould-Fogerite ◽  
L Shen ◽  
R M Woods ◽  
S Koenig ◽  
...  
Keyword(s):  
Simian Immunodeficiency Virus ◽  
Mhc Class I ◽  
Synthetic Peptide ◽  
Rhesus Monkeys ◽  
Subunit Vaccine ◽  
Class I ◽  
Target Cells ◽  
Gag Protein ◽  
Ctl Response ◽  
Immunodeficiency Virus

An effective vaccine against the human immunodeficiency virus should be capable of eliciting both an antibody and a cytotoxic T lymphocyte (CTL) response. However, when viral proteins and peptides are formulated with traditional immunological adjuvants and inoculated via a route acceptable for use in humans, they have not been successful at eliciting virus-specific, major histocompatibility complex (MHC) class I-restricted CTL. We have designed a novel viral subunit vaccine by encapsulating a previously defined synthetic peptide CTL epitope of the simian immunodeficiency virus (SIV) gag protein within a proteoliposome capable of attaching to and fusing with plasma membranes. Upon fusing, the encapsulated contents of this proteoliposome can enter the MHC class I processing pathway through the cytoplasm. In this report, we show that after a single intramuscular vaccination, rhesus monkeys develop a CD8+ cell-mediated, MHC class I-restricted CTL response that recognizes the synthetic peptide immunogen. The induced CTL also demonstrate antiviral immunity by recognizing SIV gag protein endogenously processed by target cells infected with SIV/vaccinia recombinant virus. These results demonstrate that virus-specific, MHC class I-restricted, CD8+ CTL can be elicited by a safe, nonreplicating viral subunit vaccine in a primate model for acquired immune deficiency syndrome. Moreover, the proteoliposome vaccine formation described can include multiple synthetic peptide epitopes, and, thus, offers a simple means of generating antiviral cell-mediated immunity in a genetically heterogeneous population.

CD4 Cells Engineered to Express an MHC Class I Restricted TCR Can Rescue CD8 Cells Tolerized to Tumour-Associated Antigens

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 952-952
Author(s):  
Sara Ghorashian ◽  
Ben Carpenter ◽  
Angelika Holler ◽  
Emma Nicholson ◽  
Maryam Ahmadi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Target Cells ◽  
Cd4 Cells ◽  
Cd8 Cells ◽  
Cognate Antigen ◽  
Cd4 Help

Abstract Abstract 952 Background: The efficacy of T cell therapies for cancer may be limited when targeting tumour-associated antigens (TAA) which are also self-antigens. Ongoing exposure to TAA on normal cells may lead to tolerance via anergy or exhaustion of antigen-specific T cells. Methods: We have designed a model of tolerance to TAA in which T cell receptor (TCR)-transduced CD8 T cells recognise pMDM2, a TAA that is also a ubiquitous self-antigen. CD8+ T cells were transduced with pMDM2-specific TCR (MDM-CD8) and transferred to sub-lethally irradiated B6 mice that express pMDM2 in the context of MHC Class I (H2-Kb). MDM-CD8 cells are detectable 4 weeks after transfer but show defective in vivo killing of target cells pulsed with MDM2 peptide. We have used this model to determine the mechanism of tolerance and to evaluate whether tolerant CD8+ T cells can be rescued by CD4 help. Results: To determine whether tolerance of MDM-CD8 cells was dependent upon recognition of cognate antigen, we transferred MDM-CD8 cells into mice of a different MHC background (BALB/c) which lack H2-Kb required for presentation of the TCR-recognised MDM2 peptide. When BALB/c MDM-CD8 cells were transferred to BALBc hosts their functions were preserved and they retained efficient antigen-specific cytolysis. To determine whether tolerance could be modified by provision of CD4+ T cell help, we co-transferred MDM-CD8 with transgenic OT-II CD4+ cells. OT-II cells were primed with dendritic cells (DCs) loaded with cognate pOVA323-339 or irrelevant peptide. When activated through their TCR, OT-II cells increased both the frequency of MDM2-specific CD8 cells and their cytotoxic functions, indicating that CD4 help can overcome CD8 tolerance to TAA. Ineffective antigen presentation to CD4 cells and lack of known MHC class II-restricted TAA are major limitations to providing CD4 help in T cell therapy for cancer. We therefore tested whether transfer of the MHC Class I-restricted MDM2 TCR into CD4 cells could provide help upon transfer to antigen-expressing hosts. Co-transfer of MDM2-TCR-transduced CD4 cells with CD8 cells improved antigen-specific killing of target cells when compared to single transfer of either TCR-transduced CD8 or CD4 cells. Conclusion: CD4 cells rendered capable of responding to an MHC class I restricted TAA by TCR transfer can rescue tolerance developing in a CD8 population with the same specificity. This is potentially a novel way to circumvent defective immune responses arising in adoptively transferred effector cells due to prolonged exposure to cognate antigen on normal host cells. Disclosures: Stauss: Cell Medica: Scientific Advisor Other.

Up-regulation of cytolytic functions of human Vδ2− γδ T lymphocytes through engagement of ILT2 expressed by tumor target cells

Blood ◽  
2011 ◽  
Vol 117 (10) ◽  
pp. 2864-2873 ◽  
Author(s):  
Christelle Harly ◽  
Marie-Alix Peyrat ◽  
Sonia Netzer ◽  
Julie Déchanet-Merville ◽  
Marc Bonneville ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Cytotoxic T Lymphocyte ◽  
Γδ T Cells ◽  
Class I ◽  
Antigenic Specificity ◽  
Target Cells ◽  
T Cell Clones ◽  
Cell Clones

AbstractIn humans, the majority of peripheral blood γδ T cells expresses Vγ9Vδ2 T-cell receptors (TCR) and recognize nonpeptidic phosphorylated antigens. In contrast, most tissue-derived γδ T cells, which are located mainly in spleen and epithelia, preferentially use Vδ1 or Vδ3 chains paired with diverse Vγ chains to form their TCR. Our knowledge about the antigenic specificity and costimulation requirements of human Vδ2− γδ T cells remains limited. In an attempt to address this important issue, we characterized the specificity of a monoclonal antibody (mAb 256), screened for its ability to specifically inhibit cytolytic responses of several human Vδ2− γδ T-cell clones against transformed B cells. We show that mAb 256 does not target a TCR ligand but blocks key interactions between non-TCR molecules on effector γδ T cells and ILT2 molecule, expressed by tumor targets. In line with the previously reported specificity of this NK receptor for classic and nonclassic major histocompatibility complex (MHC) class I molecules, blockade of MHC class I/ILT2 interactions using MHC class I- or ILT2-specific mAbs and ILT2-Fc molecules inhibited tumor-induced activation of Vγ8Vδ3 T-cell clones. Therefore, this study describes a new cytotoxic T lymphocyte activation pathway involving MHC class I engagement on γδ T cells.

scholarly journals Characterization of Human CD8+ T Cells Reactive with Mycobacterium tuberculosis–infected Antigen-presenting Cells

1998 ◽  
Vol 187 (10) ◽  
pp. 1633-1640 ◽  
Author(s):  
David M. Lewinsohn ◽  
Mark R. Alderson ◽  
Andria L. Briden ◽  
Stanley R. Riddell ◽  
Steven G. Reed ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Interferon Γ ◽  
Class I ◽  
Target Cells ◽  
Human Immune Response ◽  
Infected Cells ◽  
Antigen Presenting

Previous studies in murine models, including those using the β2 microglobulin knockout mouse, have suggested an important role for CD8+ T cells in host defense to Mycobacterium tuberculosis (Mtb). At present, little is understood about these cells in the human immune response to tuberculosis. This report demonstrates the existence of human Mtb-reactive CD8+ T cells. These cells are present preferentially in persons infected with Mtb and produce interferon γ in response to stimulation with Mtb-infected target cells. Recognition of Mtb-infected cells by these CD8+ T cells is restricted neither by the major histocompatibility complex (MHC) class I A, B, or C alleles nor by CD1, although it is inhibited by anti–MHC class I antibody. The Mtb-specific CD8+ T cells recognize an antigen which is generated in the proteasome, but which does not require transport through the Golgi-ER. The data suggest the possible use of nonpolymorphic MHC class Ib antigen presenting structures other than CD1.

scholarly journals Antigen-specific recognition of autologous leukemia cells and allogeneic class-I MHC antigens by IL-2-activated cytotoxic T cells from a patient with acute T-cell leukemia

Blood ◽  
1989 ◽  
Vol 74 (1) ◽  
pp. 343-353
Author(s):  
P Fisch ◽  
G Weil-Hillman ◽  
M Uppenkamp ◽  
JA Hank ◽  
BP Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Class I ◽  
Target Cells ◽  
Class I Mhc ◽  
Blood Lymphocytes ◽  
Mhc Class I Antigens

Culturing of leukemic blood lymphocytes from a patient with acute T- cell lymphoblastic leukemia (T-ALL) with interleukin-2 (IL-2) yielded T- cell line AK-1 with a remarkable cytotoxic specificity. This line mediated strong lysis of tumor target lines expressing major histocompatibility complex (MHC) class I antigens, such as Raji, CEM, and Molt-4 cells, but no killing of K562 and Daudi cells, which are deficient in MHC class I. In contrast, lymphokine-activated killer (LAK) cells from normal donors destroyed all these tumor targets, without MHC restriction. Line AK-1, originating from residual normal T cells present in the leukemic blood, lysed autologous leukemic blasts and peripheral blood lymphocytes (PBL) from many but not all allogeneic individuals but failed to kill autologous remission lymphocytes. Destruction of the autologous leukemic targets by AK-1 could be inhibited by unlabeled competitor target cells that were lysed by AK-1, but not by target cells that were not lysed. This suggests that AK-1 specifically recognized an alien determinant on the autologous ALL cells, crossreactive with allogeneic MHC class I antigens. This reactivity with some degree of tumor specificity may be a leukemic equivalent to responses reported for populations of tumor infiltrating lymphocytes (TIL) seen in some solid tumors.

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