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 Aggregation of MHC class I molecules on a CD8+α β T cell clone specifically inhibits non-antigen-specific lysis of target cells

2004 ◽  
Vol 34 (1) ◽  
pp. 47-55 ◽  
Author(s):  
Esther Caparrós ◽  
A. Beltrán de Heredia ◽  
Emilio Carpio ◽  
David Sancho ◽  
Enrique Aguado ◽  
...  
Keyword(s):  
T Cell ◽  
Mhc Class I ◽  
Cell Clone ◽  
Class I ◽  
Target Cells ◽  
Specific Lysis ◽  
T Cell Clone ◽  
Mhc Class I Molecules

scholarly journals ERAP1 Controls the Interaction of the Inhibitory Receptor KIR3DL1 With HLA-B51:01 by Affecting Natural Killer Cell Function

2021 ◽  
Vol 12 ◽  
Author(s):  
Silvia D’Amico ◽  
Valerio D’Alicandro ◽  
Mirco Compagnone ◽  
Patrizia Tempora ◽  
Giusy Guida ◽  
...  
Keyword(s):  
Mhc Class I ◽  
Cell Function ◽  
Nk Cell ◽  
Killer Cell ◽  
Cell Subset ◽  
Human Tumor ◽  
Hla Class I ◽  
Class I ◽  
Pharmacological Inhibition ◽  
Mhc Class I Molecules

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

scholarly journals A Common Inhibitory Receptor for Major Histocompatibility Complex Class I Molecules on Human Lymphoid and Myelomonocytic Cells

1997 ◽  
Vol 186 (11) ◽  
pp. 1809-1818 ◽  
Author(s):  
Marco Colonna ◽  
Francisco Navarro ◽  
Teresa Bellón ◽  
Manuel Llano ◽  
Pilar García ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
B Cells ◽  
Mhc Class I ◽  
Killer Cell ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Myelomonocytic Cells ◽  
Mhc Class I Molecules

Natural killer (NK) cell–mediated lysis is negatively regulated by killer cell inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules. In this study, we characterize a novel inhibitory MHC class I receptor of the immunoglobulin-superfamily, expressed not only by subsets of NK and T cells, but also by B cells, monocytes, macrophages, and dendritic cells. This receptor, called Ig-like transcript (ILT)2, binds MHC class I molecules and delivers a negative signal that inhibits killing by NK and T cells, as well as Ca2+ mobilization in B cells and myelomonocytic cells triggered through the B cell antigen receptor and human histocompatibility leukocyte antigens (HLA)–DR, respectively. In addition, myelomonocytic cells express receptors homologous to ILT2, which are characterized by extensive polymorphism and might recognize distinct HLA class I molecules. These results suggest that diverse leukocyte lineages have adopted recognition of self–MHC class I molecules as a common strategy to control cellular activation during an immune response.

Leukemic Blasts Acting as Host Antigen Presenting Cells Trigger a Combined CD4 and CD8 Allo-Immune Response Directed Against Mismatched HLA Class I.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5030-5030
Author(s):  
Avital Amir ◽  
Renate S. Hagendoorn ◽  
Erik W.A. Marijt ◽  
Roelof Willemze ◽  
J.H. Frederik Falkenburg ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Class I ◽  
Mixed Chimerism ◽  
Target Cells ◽  
Hla Dr ◽  
Donor T Cells

Abstract Single HLA locus mismatched stem cell transplantation (SCT) is applied in patients with hematological malignancies who may benefit from allogeneic transplantation but lack an HLA-matched donor. Although HLA disparity between patient and donor increases the risk of developing GVHD, the relative risk of GVHD after single HLA locus mismatched SCT is only 1.5 fold. In view of the high frequency of allo-HLA reactive T-cells, which is about 1000-fold higher than the frequencies of minor histocompatibility antigen specific T-cells, this risk increase is lower than could be expected. Since almost all nucleated cells express HLA class I, one would expect all single HLA class I mismatched transplanted patients to develop severe GVHD. We hypothesized therefore that the presentation of the HLA class I mismatched allele on nucleated cells of the patient is not sufficient to elicit an effective allo-immune response. We characterized the allo-immune response in a patient with acute myeloid leukemia (AML) who was treated with a T-cell depleted SCT from a sibling donor who was HLA identical except for an HLA-A2 crossover. Six months after SCT, donor lymphocyte infusion (DLI) of 2.5*10e6 T-cells/kg was given for mixed chimerism comprising 99% T-cells of patient origin. No clinical response and no GVHD developed. Twelve months after SCT 95% of T-cells were still of patient origin, and AML relapse occurred with 9% blasts in bone marrow for which a second DLI containing 7.5*10e6 T-cells/kg was given. Five weeks after the DLI the patient died of grade IV GVHD. During the GVHD, conversion to donor chimerism developed. In peripheral blood of the patient 90% of CD8 and 40% of CD4 donor T-cells were activated as determined by HLA-DR expression. To analyze the nature of the immune response, the activated CD8 and CD4 donor T-cells were single cell sorted, expanded and tested for alloreactivity and HLA restriction using cytotoxicity and cytokine production assays against a panel of target cells blocked with different HLA-mAbs. 82% of the CD8 T-cell clones were alloreactive and restricted to the allo-HLA-A2. The response was highly polyclonal as shown by the usage of different T-cell receptor Vβ chains with different CDR3 sequences. 26% of the CD4 clones were alloreactive and this response was also polyclonal. The CD4 clones were HLA-DR1 restricted and recognized donor EBV-LCL transduced with HLA-A2, indicating that the peptide recognized in HLA-DR1 was derived from the mismatched HLA-A2 molecule. The recognized epitope was demonstrated to comprise AA 103–120 derived from a hypervariable region of HLA-A2. At the time of the first DLI, only HLA class I expressing T-cells and non-hematopoietic patient derived cells were present, capable of activating the CD8 T-cells but not of triggering the CD4 response. Leukemic blasts present at the time of the second DLI, however, expressed both HLA-DR and HLA class I, and were shown to activate the CD4 as well as the CD8 clones. We hypothesize that the HLA class II expression on hematopoietic cells of the patient at the time of the relapse was essential for the development of this immune response. In conclusion, these results indicate a role for patient leukemic blasts acting as host APCs in initiating the GVH response by activating both a CD4 and CD8 T-cell response in an HLA class I mismatched setting.

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.

Empty peptide-receptive MHC class I molecules for efficient detection of antigen-specific T cells

2019 ◽  
Vol 4 (37) ◽  
pp. eaau9039 ◽  
Author(s):  
Sunil Kumar Saini ◽  
Tripti Tamhane ◽  
Raghavendra Anjanappa ◽  
Ankur Saikia ◽  
Sofie Ramskov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mhc Class I ◽  
Single Step ◽  
Class I ◽  
Cell Detection ◽  
Wild Type ◽  
Efficient Detection ◽  
Cell Immunity ◽  
Mhc Class I Molecules

The peptide-dependent stability of MHC class I molecules poses a substantial challenge for their use in peptide-MHC multimer–based approaches to comprehensively analyze T cell immunity. To overcome this challenge, we demonstrate the use of functionally empty MHC class I molecules stabilized by a disulfide bond to link the α1 and α2 helices close to the F pocket. Peptide-loaded disulfide-stabilized HLA-A*02:01 shows complete structural overlap with wild-type HLA-A*02:01. Peptide-MHC multimers prepared using disulfide-stabilized HLA-A*02:01, HLA-A*24:02, and H-2Kb can be used to identify antigen-specific T cells, and they provide a better staining index for antigen-specific T cell detection compared with multimers prepared with wild-type MHC class I molecules. Disulfide-stabilized MHC class I molecules can be loaded with peptide in the multimerized form without affecting their capacity to stain T cells. We demonstrate the value of empty-loadable tetramers that are converted to antigen-specific tetramers by a single-step peptide addition through their use to identify T cells specific for mutation-derived neoantigens and other cancer-associated antigens in human melanoma.

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 Evolution and Immunogenetics of Natural Killer Cell Receptors in Health and Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. SCI-25-SCI-25
Author(s):  
Peter Parham
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Mhc Class I ◽  
Nk Cell ◽  
Killer Cell ◽  
Hla Class I ◽  
Class I ◽  
Mhc Class I Molecules ◽  
Kir Gene ◽  
Kir Haplotypes

Abstract Natural killer (NK) cells are phenotypically diverse lymphocytes that contribute to innate immunity, adaptive immunity and placental reproduction. Unlike B and T cells, NK cells do not use rearranging genes to make diverse antigen receptors that are clonally expressed. Instead, NK cells express diverse combinations of a variety of receptors that are encoded by conventional non-rearranging genes. Several of these receptors are specific for conserved and variable determinants of major histocompatibility complex (MHC) class I molecules. In humans, the killer-cell immunoglobulin-like receptors (KIR) are a diverse and polymorphic family of NK-cell receptors that recognize determinants of human leukocyte antigen (HLA)-A, B and C, the polymorphic human MHC class I molecules. HLA-A, B and C are the most polymorphic of human genes, and they correlate with susceptibility to a wide range of diseases and clinical outcomes, including allogeneic hematopoietic cell transplantation (HCT). During NK-cell development, interactions between epitopes of HLA class I and KIR educate the NK cells to recognize the normal expression of these epitopes on healthy cells, and to respond to unhealthy cells in which that expression is perturbed. In the context of HCT, certain types of HLA class I mismatch enable donor-derived NK cells to make an alloreactive and beneficial graft-versus-leukemia response. Although it is likely that all placental mammals have NK cells, only a small minority of these species has a diverse KIR family like that in humans. These comprise the simian primates: New World monkeys, Old World monkeys and the great apes. Under pressure from diverse and rapidly evolving pathogens, both the MHC class I and KIR gene families have been driven to evolve rapidly. Consequently, much of their character is species-specific. This is especially true for the human KIR gene family, which is qualitatively different from that of our closest relatives, the chimpanzees. Whereas chimpanzee KIR haplotype diversity represents variations on a theme of genes encoding robust MHC class I receptors, humans have an even balance between group A KIR haplotypes encoding robust HLA class I receptors and group B KIR haplotypes encoding receptors that, to varying degree, have been subject to natural selection for reduced functional recognition of HLA class I. A balance of A and B is present in all human populations and thus appears essential for the long-term survival and competitiveness of human communities. Whereas the A KIR haplotypes correlate with successful defense against viral infection, maternal B KIR haplotypes correlate with reproductive success and donor B KIR haplotypes improve the outcome of allogeneic HCT as therapy for acute myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

Immunotargetting of the Wilms’ Tumor WT1 Antigen for Dendritic Cell and B-Cell-Based Vaccination of Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2541-2541
Author(s):  
Zwi N. Berneman ◽  
Ann Van Driessche ◽  
Peter Ponsaerts ◽  
Liquan Gao ◽  
Hans J. Stauss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Dendritic Cell ◽  
Mhc Class I ◽  
Wilms Tumor ◽  
Cell Clone ◽  
Class I ◽  
T Cell Clone

Abstract The Wilms’ tumor antigen (WT1) is overexpressed in almost all leukemias and in several solid tumors. Overexpression of WT1 blocks the normal differentiation and enhances proliferation of hematopoietic progenitor cells. WT1 is also used in the detection of minimal residual disease. Using WT1-specific MHC class I tetramers, we were able to detect ex vivo low numbers of WT1-specific CD8+ T cells in the peripheral blood or bone marrow of leukemia patients, but not of healthy donors. In one particular donor we could detect up to 24% WT1 tetramer positive cells at the time of diagnosis. WT1 tetramer positive cells were present in all types of leukemia, except for CLL, and also in patients with MDS. Because WT1 plays an important role in leukemogenesis, it could serve as an antigenic target for dendritic cell-based immunotherapy. We used the mRNA electroporation strategy that allows presentation of multiple WT1 epitopes by MHC class I molecules, irrespective of the HLA haplotype. Monocyte-derived DC (Mo-DC) were electroporated with in vitro transcribed WT1 mRNA. RT-PCR and Western blot analysis showed that WT1 RNA and protein, respectively, was present for up to 5 days in WT1-electroporated DC, but not in mock- or EGFP mRNA-electroporated Mo-DC. Importantly, using a CD8+ T cell clone that secretes IFN-gamma upon recognizing the HLA-A2 immunodominant WT1126–134 epitope, we showed that WT1 mRNA-electroporated Mo-DC processed the WT1 protein via the MHC class I pathway and presented the WT1 epitope to the T cells in an HLA- and antigen-specific manner. Since Mo-DCs are a non-expandable source of antigen-presenting cells, we also used proliferating CD40-activated B (CD40-B) cells as inducers for WT1-specific T cell immunity. CD40-B cells were expanded to high numbers from a limited amount of peripheral blood and subsequently electroporated with WT1 mRNA. In T cell clone activation experiments, WT1 mRNA-electroporated CD40-B cells were as efficient as Mo-DC in presenting the WT1 epitope in a MHC class I-restricted manner. Based on these results, we are currently focusing on the in vitro (re)activation of autologous WT1-specific cytotoxic T cells of leukemia patients using WT1-loaded autologous Mo-DC or CD40-B cells and on the immunological parameters to break immune tolerance against the WT1 tumor self antigen.

Sign in / Sign up

Export Citation Format

Share Document