Direct Alloreactivity by Human Cytotoxic T Lymphocytes Can Be Inhibited by Altered Peptide Ligand Antagonism

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 1020-1024 ◽  
Author(s):  
Scott R. Burrows ◽  
Rajiv Khanna ◽  
Denis J. Moss
Keyword(s):  
Cytochrome P450 ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Allograft Rejection ◽  
Single Amino Acid ◽  
Peptide Ligand ◽  
Target Cells ◽  
Altered Peptide Ligand ◽  
Altered Peptide Ligands ◽  
Mhc Molecules

Abstract Alloreactive T lymphocytes that respond directly to foreign major histocompatibility complex (MHC) molecules and bound peptide are known to be central mediators of graft-versus-host disease (GVHD) and allograft rejection. We have recently identified a peptide from the human protein, cytochrome P450 (isotypes IIC9, 10, or 18), that is recognized in association with human leukocyte antigen (HLA) B*3501 by alloreactive cytotoxic T lymphocytes (CTLs). These CTLs with this specificity were isolated from several unrelated individuals and were found to express a common T-cell receptor (TCR). Synthetic analogs of the cytochrome P450 peptide were generated by introducing single amino acid substitutions at putative TCR contact positions. Four altered peptide ligands were powerful competitive antagonists of these CTL clones, reducing lysis levels of target cells expressing the alloantigen HLA B*3501 by over 80%. This first demonstration that it is possible to suppress CTL alloreactivity with structural variants of allodeterminants raises the prospect that such TCR antagonists could be exploited within the clinical arena to specifically modulate GVHD and allograft rejection.

Direct Alloreactivity by Human Cytotoxic T Lymphocytes Can Be Inhibited by Altered Peptide Ligand Antagonism

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 1020-1024
Author(s):  
Scott R. Burrows ◽  
Rajiv Khanna ◽  
Denis J. Moss
Keyword(s):  
Cytochrome P450 ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Allograft Rejection ◽  
Single Amino Acid ◽  
Peptide Ligand ◽  
Target Cells ◽  
Altered Peptide Ligand ◽  
Altered Peptide Ligands ◽  
Mhc Molecules

Alloreactive T lymphocytes that respond directly to foreign major histocompatibility complex (MHC) molecules and bound peptide are known to be central mediators of graft-versus-host disease (GVHD) and allograft rejection. We have recently identified a peptide from the human protein, cytochrome P450 (isotypes IIC9, 10, or 18), that is recognized in association with human leukocyte antigen (HLA) B*3501 by alloreactive cytotoxic T lymphocytes (CTLs). These CTLs with this specificity were isolated from several unrelated individuals and were found to express a common T-cell receptor (TCR). Synthetic analogs of the cytochrome P450 peptide were generated by introducing single amino acid substitutions at putative TCR contact positions. Four altered peptide ligands were powerful competitive antagonists of these CTL clones, reducing lysis levels of target cells expressing the alloantigen HLA B*3501 by over 80%. This first demonstration that it is possible to suppress CTL alloreactivity with structural variants of allodeterminants raises the prospect that such TCR antagonists could be exploited within the clinical arena to specifically modulate GVHD and allograft rejection.

Immune evasion in malaria: altered peptide ligands of the circumsporozoite protein

Parasitology ◽  
1997 ◽  
Vol 115 (7) ◽  
pp. 55-66 ◽  
Author(s):  
M. PLEBANSKI ◽  
E. A. M. LEE ◽  
A. V. S. HILL
Keyword(s):  
T Cells ◽  
Cytotoxic T Cells ◽  
Peptide Ligands ◽  
Circumsporozoite Protein ◽  
Peptide Ligand ◽  
Altered Peptide Ligand ◽  
Amino Acid Residues ◽  
Liver Stage ◽  
Altered Peptide Ligands ◽  
Mhc Molecules

T cells are central to immunity in malaria. CD4+ helper T cells favour the generation of high-affinity antibodies that are effective against blood stages and they are necessary to establish immunological memory. The intrahepatic stage of infection can be eliminated by specific CD8+ cytotoxic T cells (CTL). Cytokines secreted by CD4+ T cells may also contribute to liver stage immunity. Evolution has selected varied mechanisms in pathogens to avoid recognition by T cells. T cells recognize foreign epitopes as complexes with host major histocompatibility (MHC) molecules. Thus, a simple form of evasion is to mutate amino acid residues which allow binding to an MHC allele. Recently, more sophisticated forms of polymorphic evasion have been described. In altered peptide ligand (APL) antagonism, the concurrent presentation of particular closely related epitope variants can prevent memory T cell effector functions such as cytotoxicity, lymphokine production and proliferation. In immune interference, the effect of the concurrent presentation of such related epitope variants can go a step further and prevent the induction of memory T cells from naive precursors. The analysis of immune responses to a protein of P. falciparum, the circumsporozoite protein (CSP), indicates that the malaria parasite may utilize these evasion strategies.

scholarly journals Peptide-independent Recognition by Alloreactive Cytotoxic T Lymphocytes (CTL)

1997 ◽  
Vol 185 (6) ◽  
pp. 1023-1034 ◽  
Author(s):  
Pamela A. Smith ◽  
Anders Brunmark ◽  
Michael R. Jackson ◽  
Terry A. Potter
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Skin Graft ◽  
Antigen Processing ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Mhc Molecules ◽  
Alloreactive T Cells

We have isolated several H-2Kb–alloreactive cytotoxic T cell clones and analyzed their reactivity for several forms of H-2Kb. These cytotoxic T lymphocytes (CTL) were elicited by priming with a skin graft followed by in vitro stimulation using stimulator cells that express an H-2Kb molecule unable to bind CD8. In contrast to most alloreactive T cells, these CTL were able to recognize H-2Kb on the surface of the antigen processing defective cell lines RMA-S and T2. Furthermore, this reactivity was not increased by the addition of an extract containing peptides from C57BL/6 (H-2b) spleen cells, nor was the reactivity decreased by treating the target cells with acid to remove peptides bound to MHC molecules. The CTL were also capable of recognizing targets expressing the mutant H-2Kbm8 molecule. These findings suggested that the clones recognized determinants on H-2Kb that were independent of peptide. Further evidence for this hypothesis was provided by experiments in which H-2Kb produced in Drosophila melanogaster cells and immobilized on the surface of a tissue culture plate was able to stimulate hybridomas derived from these alloreactive T cells. Precursor frequency analysis demonstrated that skin graft priming, whether with skin expressing the wild-type or the mutant H-2Kb molecule, is a strong stimulus to elicit peptide-independent CTL. Moreover, reconstitution experiments demonstrated that the peptide-independent CTL clones were capable of mediating rapid and complete rejection of H-2–incompatible skin grafts. These findings provide evidence that not all allorecognition is peptide dependent.

scholarly journals HLA restriction of human cytotoxic T lymphocytes specific for influenza virus. Poor recognition of virus associated with HLA A2.

1978 ◽  
Vol 148 (6) ◽  
pp. 1458-1467 ◽  
Author(s):  
A McMichael
Keyword(s):  
Influenza Virus ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Influenza A ◽  
Human Peripheral Blood ◽  
Peripheral Blood Lymphocytes ◽  
The Other ◽  
Target Cells ◽  
Surface Molecules ◽  
Human Peripheral Blood Lymphocytes

Cytotoxic T lymphocytes (CTL), specific for influenza A/X31 virus, were generated from human peripheral blood lymphocytes. These CTL lysed target cells that were infected with the same virus and that shared HLA A or B locus antigens. Minimal lysis was observed when HLA-D antigens were shared. Not all HLA A and B antigens were equally effective. Efficient lysis of target cells was seen when HLA A1, A3, B7, B8, B27 and BW21 were shared with the CTL, but when HLA A2 was the only shared antigen lysis was usually minimal. This deficiency in CTL function associated with HLA A2 was not absolute. It is suggested that the function of this antigen might be influenced by other surface molecules on the cell and in particular the other HLA products.

N-linked oligosaccharides can protect target cells from the lysis mediated by NK cells but not by cytotoxic T lymphocytes: role of NKG2-A

1999 ◽  
Vol 54 (2) ◽  
pp. 113-121 ◽  
Author(s):  
M.-A. Sol ◽  
N. Vacaresse ◽  
J. Lule ◽  
C. Davrinche ◽  
B. Gabriel ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Nk Cells ◽  
Cytotoxic T Lymphocytes ◽  
Target Cells

scholarly journals Extracellular Cystatin F Is Internalised by Cytotoxic T Lymphocytes and Decreases Their Cytotoxicity

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3660
Author(s):  
Mateja Prunk ◽  
Milica Perišić Nanut ◽  
Tanja Jakoš ◽  
Jerica Sabotič ◽  
Urban Švajger ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Cathepsin L ◽  
Killer Cell ◽  
Full Length ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Natural Killer Cell Cytotoxicity ◽  
Cathepsin C ◽  
Cysteine Cathepsins

Cystatin F is a protein inhibitor of cysteine cathepsins, peptidases involved in the activation of the effector molecules of the perforin/granzyme pathway. Cystatin F was previously shown to regulate natural killer cell cytotoxicity. Here, we show that extracellular cystatin F has a role in regulating the killing efficiency of cytotoxic T lymphocytes (CTLs). Extracellular cystatin F was internalised into TALL-104 cells, a cytotoxic T cell line, and decreased their cathepsin C and H activity. Correspondingly, granzyme A and B activity was also decreased and, most importantly, the killing efficiency of TALL-104 cells as well as primary human CTLs was reduced. The N-terminally truncated form of cystatin F, which can directly inhibit cathepsin C (unlike the full-length form), was more effective than the full-length inhibitor. Furthermore, cystatin F decreased cathepsin L activity, which, however, did not affect perforin processing. Cystatin F derived from K-562 target cells could also decrease the cytotoxicity of TALL-104 cells. These results clearly show that, by inhibiting cysteine cathepsin proteolytic activity, extracellular cystatin F can decrease the cytotoxicity of CTLs and thus compromise their function.

Non-infectious virus induces cytotoxic T lymphocytes and binds to target cells to permit their lysis

Nature ◽  
1977 ◽  
Vol 269 (5629) ◽  
pp. 595-597 ◽  
Author(s):  
JON C. PALMER ◽  
LEON J. LEWANDOWSKI ◽  
DAVID WATERS
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Infectious Virus ◽  
Target Cells

Molecular Basis of Lymphocyte-Mediated Destruction of Traget Cells

Physiology ◽  
1988 ◽  
Vol 3 (5) ◽  
pp. 211-216
Author(s):  
JD-E Young ◽  
ZA Cohn
Keyword(s):  
Natural Killer Cells ◽  
T Lymphocytes ◽  
Natural Killer ◽  
Cytotoxic T Lymphocytes ◽  
Immune Cells ◽  
Molecular Basis ◽  
Target Cells ◽  
Killer Cells

Subsets of lymphocytes, known as cytotoxic T lymphocytes or natural killer cells, are potent killers of target cells. These immune cells have large granules in their cytoplasm containing cytotoxic peptides and other factors. Several of these molecules have been isolated and their functions elucidated.

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