scholarly journals Immunologic recognition of influenza virus-infected cells. II. Expression of influenza A matrix protein on the infected cell surface and its role in recognition by cross-reactive cytotoxic T cells

1977 ◽  
Vol 146 (3) ◽  
pp. 673-689 ◽  
Author(s):  
TJ Braciale
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cell Surface ◽  
Infected Cell ◽  
Virus Strain ◽  
Influenza A ◽  
Matrix Protein ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Target Cells

Two distinct subpopulations of cytotoxic T cells are generated in the primary or secondary response of mice to type A influenza viruses. One subpopulation is specific for the immunizing virus strain. The other subpopulation shows a high degree of cross-reactivity for heterologous type A virus of a different subtype. This report examines the possibility that distinct influenza virus antigens, expressed on the surface of the infected cell, are recognized by the different subpopulations of influenza-specific cytotoxic T cells. Data are presented which demonstrate that influenza A matrix protein, an internal virion antigen, is detectable on the surface of target cells infected with influenza A viruses of different subtypes. Since this viral antigen is type specific, i.e., serologically cross-reactive among all type A influenza viruses, it could serve as the target for cross-reactive cytotoxic T cells. To further examine the specificity of the two cytotoxic T-cell subpopulations, experiments were carried out by using the inhibitor of glycoprotein synthesis - 2-Deoxy-D-Glucose 2-DG. These experiments examine first the effect of 2-DG on the expression of influenza matrix protein and viral glycoprotein on the infected cell surface and second, the susceptibility of 2-DG-treated target cells to lysis by cytotoxic T cells. 2-DG inhibits the expression of the viral hemagglutinin glycoprotein on the cell surface but does not inhibit the expression of the nonglycosylated matrix protein. Furthermore, inhibition of glycoprotein synthesis in infected target cells abrogates the reactivity of infected target cells to lysis by virus strain-specific but not cross- reactive cytotoxic T cells. These findings suggest that the influenza glycoproteins (hemagglutinin and/or neuraminidase) and the nonglycosylated matrix protein are the targets for the virus strain- specific and cross-reactive cytotoxic T cells, respectively. These results are discussed in the light of available information on influenza virus structure and the biology of influenza infection and in terms of current models for cytotoxic T-cell recognition of virus-infected cells.

scholarly journals Biological properties of an influenza A virus-specific killer T cell clone. Inhibition of virus replication in vivo and induction of delayed-type hypersensitivity reactions.

1981 ◽  
Vol 154 (2) ◽  
pp. 225-234 ◽  
Author(s):  
Y L Lin ◽  
B A Askonas
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Influenza Infection ◽  
Type A ◽  
Biological Properties ◽  
Influenza Viruses ◽  
Delayed Type Hypersensitivity ◽  
Hypersensitivity Skin

We tested two biological properties of a continuously growing mouse cytotoxic T cell line, L4, which is specific for influenza A virus and has been cloned and recloned many times. We previously reported that L4 cells are H-2 restricted and cross-reactive for all type A influenza viruses, whereas they do not recognize type B influenza viruses. They bear Thy-1 and Lyt-2 markers. In the present study, we show that L4 cytotoxic T cells protect mice against a lethal influenza infection on transfer to syngeneic recipients, and reduce virus titers in the lungs of mice challenged with a heterologous type A influenza virus. This provides further support for the active role of cytotoxic T cells in limiting virus replication in influenza infection. We could also demonstrate that the cloned cytotoxic T cells induce a delayed-type hypersensitivity skin reaction in the footpads of mice challenged with live or inactivated influenza virus. This reaction can be observed at 24 h, but has declined by 48 h. A clone of cells derived from L4 that has lost its cytotoxic potential and its ability to recognize infected cells did not induce a delayed-type hypersensitivity reaction in the presence of virus. Thus, cytotoxic T cells actively killing influenza virus-infected cells are able to induce a delayed-type hypersensitivity skin reaction to homologous and heterologous type A influenza viruses.

scholarly journals Quantitation of influenza virus antigens on infected target cells and their recognition by cross-reactive cytotoxic T cells.

1980 ◽  
Vol 151 (5) ◽  
pp. 1014-1025 ◽  
Author(s):  
C J Hackett ◽  
B A Askonas ◽  
R G Webster ◽  
K van Wyke
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Influenza Virus ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Protein Molecule ◽  
M Protein ◽  
Target Cells ◽  
Infected Cells

Monoclonal antibody to type-A influenza virus matrix (M)-protein was used to quantitate the appearance of M-protein on abortively infected P815 cells. After 16 h of infection with different type-A viruses, only a low amount of M-protein appears on the surface of infected cells (approximately 10(3) site/cell) in contrast to approximately 10(5) hemagglutinin molecules on each cell surface. However, virus replication is required for M-protein appearance. Analysis of solubilized membranes purified from 16-h-infected cells shows approximately 10(4) M-protein molecule/cell in the plasma membrane, a content that is consistent with the observed low surface expression, and that indicates that most of the M-protein is localized internally. We found no evidence that cross-reactive cytotoxic T cells could recognize M-protein; neither monoclonal antibody or hyperimmune anti-M-protein antiserum could inhibit T cell killing, either alone or in combination with monoclonal anti-H-2 antibody. Taken together, the low level of M-protein appearance and lack of T cell blocking by anti-M-protein antibody leaves doubt that M-protein is the antigen recognized by cross-reactive cytotoxic T cells.

scholarly journals The influenza A virus nucleoprotein gene controls the induction of both subtype specific and cross-reactive cytotoxic T cells.

1984 ◽  
Vol 160 (2) ◽  
pp. 552-563 ◽  
Author(s):  
A R Townsend ◽  
J J Skehel
Keyword(s):  
T Cells ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Spleen Cells ◽  
Influenza A Viruses ◽  
Group A ◽  
Selection Of

Using genetically typed recombinant influenza A viruses that differ only in their genes for nucleoprotein, we have demonstrated that repeated stimulation in vitro of C57BL/6 spleen cells primed in vivo with E61-13-H17 (H3N2) virus results in the selection of a population of cytotoxic T lymphocytes (CTL) whose recognition of infected target cells maps to the gene for nucleoprotein of the 1968 virus. Influenza A viruses isolated between 1934 and 1979 fall into two groups defined by their ability to sensitize target cells for lysis by these CTL: 1934-1943 form one group (A/PR/8/34 related) and 1946-1979 form the second group (A/HK/8/68 related). These findings complement and extend our previous results with an isolated CTL clone with specificity for the 1934 nucleoprotein (27, 28). It is also shown that the same spleen cells derived from mice primed with E61-13-H17 virus in vivo, but maintained in identical conditions by stimulation with X31 virus (which differs from the former only in the origin of its gene for NP) in vitro, results in the selection of CTL that cross-react on target cells infected with A/PR/8/1934 (H1N1) or A/Aichi/1968 (H3N2). These results show that the influenza A virus gene for NP can play a role in selecting CTL with different specificities and implicate the NP molecule as a candidate for a target structure recognized by both subtype-directed and cross-reactive influenza A-specific cytotoxic T cells.

scholarly journals Antibody to influenza virus matrix protein detects a common antigen on the surface of cells infected with type A influenza viruses.

1977 ◽  
Vol 146 (3) ◽  
pp. 690-697 ◽  
Author(s):  
W E Biddison ◽  
P C Doherty ◽  
R G Webster
Keyword(s):  
Influenza Virus ◽  
Matrix Protein ◽  
Type A ◽  
Cross Reactivity ◽  
T Cell Response ◽  
Influenza Viruses ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Common Antigen ◽  
Infected Cells

Antisera to the type-specific internal influenza virus matrix (M) protein of a type A influenza virus were produced in goats. In the presence of complement, anti-M serum was cytotoxic for target cells which were infected with a variety of serologically distinct type A influenza viruses, but did not react with type B influenza virus-infected cells. Absorption experiments indicated that anti-M serum detected a common antigen(s) on the surface of type A-infected cells. This serological cross-reactivity parallels the cross-reactivity observed for the cytotoxic T-cell response to type A viruses.

scholarly journals Specificity of cytotoxicity T cells directed to influenza virus hemagglutinin.

1979 ◽  
Vol 149 (4) ◽  
pp. 856-869 ◽  
Author(s):  
T J Braciale
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Cross Reactivity ◽  
Cytotoxic T Cell ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Induction

Purified type A influenza viral hemagglutinin stimulates an in vitro cell-mediated cytotoxic cell response that exhibits a high degree of specificity for the immunizing hemagglutinin. The response magnitude is proportional to the hemagglutinin dose used for stimulation. The lytic activity of the effector cells is H-2 restricted. Analysis of the specificity of the response indicated that these cytotoxic T cells readily distinguish target cells expressing serologically unrelated hemagglutinin from target cells bearing hemagglutinins serologically related to the stimulating hemagglutinin. Further analysis of the fine specificity of cytotoxic T-cell recognition with serologically cross-reactive type A influenza hemagglutinins revealed a hierarchy of cross-reactivity among these hemagglutinins that was the converse of the serologic hierarchy. These results are discussed in terms of possible differences and similarities in the specificity repertoire of cytotoxic T cells and antibodies. Possible implications of these findings from the standpoint of cytotoxic T-cell induction are also discussed.

scholarly journals Cross-Reactivity between Hepatitis C Virus and Influenza A Virus Determinant-Specific Cytotoxic T Cells

2001 ◽  
Vol 75 (23) ◽  
pp. 11392-11400 ◽  
Author(s):  
Heiner Wedemeyer ◽  
Eishiro Mizukoshi ◽  
Anthony R. Davis ◽  
Jack R. Bennink ◽  
Barbara Rehermann
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Influenza A Virus ◽  
Influenza A ◽  
Blood Donors ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Memory Cells

ABSTRACT The cellular immune response contributes to viral clearance as well as to liver injury in acute and chronic hepatitis C virus (HCV) infection. An immunodominant determinant frequently recognized by liver-infiltrating and circulating CD8+ T cells of HCV-infected patients is the HCVNS3-1073 peptide CVNGVCWTV. Using a sensitive in vitro technique with HCV peptides and multiple cytokines, we were able to expand cytotoxic T cells specific for this determinant not only from the blood of 11 of 20 HCV-infected patients (55%) but also from the blood of 9 of 15 HCV-negative blood donors (60%), while a second HCV NS3 determinant was recognized only by HCV-infected patients and not by seronegative controls. The T-cell response of these healthy blood donors was mediated by memory T cells, which cross-reacted with a novel T-cell determinant of the A/PR/8/34 influenza A virus (IV) that is endogenously processed from the neuraminidase (NA) protein. Both the HCV NS3 and the IV NA peptide displayed a high degree of sequence homology, bound to the HLA-A2 molecule with high affinity, and were recognized by cytotoxic T lymphocytes with similar affinity (10−8 M). Using the HLA-A2-transgenic mouse model, we then demonstrated directly that HCV-specific T cells could be induced in vivo by IV infection. Splenocytes harvested from IV-infected mice at the peak of the primary response (day 7 effector cells) or following complete recovery (day 21 memory cells) recognized the HCV NS3 peptide, lysed peptide-pulsed target cells, and produced gamma interferon. These results exemplify that host responses to an infectious agent are influenced by cross-reactive memory cells induced by past exposure to heterologous viruses, which could have important consequences for vaccine development.

scholarly journals Identification of viral molecules recognized by influenza-specific human cytotoxic T lymphocytes.

1987 ◽  
Vol 165 (2) ◽  
pp. 408-416 ◽  
Author(s):  
F Gotch ◽  
A McMichael ◽  
G Smith ◽  
B Moss
Keyword(s):  
Influenza Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Viral Proteins ◽  
Target Cells ◽  
Gene Products ◽  
Virus Surface ◽  
Vaccinia Viruses ◽  
The Matrix

Human cytotoxic T cells specific for influenza A virus were tested for recognition of each of the ten influenza A virus proteins expressed in target cells using recombinant vaccinia viruses. They recognized the matrix M1, polymerase PB2, and nucleoproteins of influenza virus in association with MHC class I antigens. These internal viral proteins were seen by CTL in conjunction with one or more of the available dependent HLA gene products. There was no detectable recognition of influenza virus surface glycoproteins in target cells.

Cytotoxic T cells kill influenza virus infected cells but do not distinguish between serologically distinct type A viruses

Nature ◽  
1977 ◽  
Vol 267 (5609) ◽  
pp. 354-356 ◽  
Author(s):  
H. J. ZWEERINK ◽  
S. A. COURTNEIDGE ◽  
J. J. SKEHEL ◽  
M. J. CRUMPTON ◽  
BRIGITTE A. ASKONAS
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cytotoxic T Cells ◽  
Distinct Type ◽  
Type A ◽  
Infected Cells

scholarly journals Induction of virus-specific modifications recognized by cytotoxic T cells is not altered by prior substitution of target cells with trinitrophenol.

1977 ◽  
Vol 146 (2) ◽  
pp. 617-622 ◽  
Author(s):  
W E Biddison ◽  
H R Snodgrass ◽  
J Bennink ◽  
R B Effros ◽  
P C Doherty
Keyword(s):  
T Cells ◽  
Cell Membrane ◽  
Influenza A ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Influenza A Viruses ◽  
Infected Cells

Cytotoxic thymus-derived lymphocytes generated after interaction with trinitrophenyl (TNP)-substituted or virus-infected cells only lyse H-2 compatible target cells modified with the component used to immunize (TNP or virus). Prior saturation of TNP-reactive sites inhibits neither the infectivity of influenza A viruses, nor the capacity of infected cells to develop antigenic changes recognized by influenza-immune T cells. The two antigens are distinct entities on the cell membrane and do not obviously compete to form interactions with H-2 molecules.

Cytotoxic T cells to type A influenza virus; viral hemagglutinin induces A-strain specificity while infected cells confer cross-reactive cytotoxicity

1977 ◽  
Vol 7 (9) ◽  
pp. 630-635 ◽  
Author(s):  
H.J. Zweerink ◽  
Brigitte A. Askonas ◽  
Dianne Millican ◽  
Sara A. Courtneidge ◽  
J.J. Skehel
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cytotoxic T Cells ◽  
Type A ◽  
Strain Specificity ◽  
Viral Hemagglutinin ◽  
Infected Cells
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