Significance of the six peptide-binding pockets of HLA-A2.1 in influenza a matrix peptide-specific cytotoxic T-lymphocyte reactivity

1994 ◽  
Vol 41 (2) ◽  
pp. 160-166 ◽  
Author(s):  
Masanori Matsui ◽  
Robert J. Moots ◽  
Andrew J. McMichael ◽  
Jeffrey A. Frelinger
Keyword(s):  
T Lymphocyte ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Peptide Binding ◽  
Binding Pockets ◽  
Hla A2.1 ◽  
Lymphocyte Reactivity

scholarly journals Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment.

1995 ◽  
Vol 181 (1) ◽  
pp. 79-91 ◽  
Author(s):  
P J Lehner ◽  
E C Wang ◽  
P A Moss ◽  
S Williams ◽  
K Platt ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Gene Segment ◽  
Cell Subpopulation ◽  
Specific Lysis ◽  
Ctl Response ◽  
The Matrix ◽  
Limiting Dilution

The major histocompatibility complex class I-restricted cytotoxic T lymphocyte (CTL) response is important in the clearance of viral infections in humans. After influenza A infection, a peptide from the matrix protein, M58-66, is presented in the context of the MHC allele HLA-A0201 and the resulting CTL response is detectable in most HLA-A0201 subjects. An initial study suggested that M58-66-specific CTL clones show conserved T cell receptor (TCR) alpha and beta gene segments. We have addressed the significance of this observation by determining the expression of V beta 17 during the development of M58-66-specific CTL lines in 21 unrelated HLA-A0201 subjects, and analyzing TCR usage by M58-66-specific CTL clones. TCR V beta 17 was the dominant V beta segment used and CD8 V beta 17 expansion correlated with M58-66-specific lysis. Limiting dilution analysis from five subjects showed the M58-66 CTL precursor frequency to vary between 1/54,000 and less than 1/250,000, and that up to 85% of the matrix peptide (M58-66)-specific CTL used the V beta 17 gene segment. The M58-66 specific CTL response was dependent on previous viral exposure and specific V beta 17 expansion, as it was not found in cord blood, despite a readily expandable V beta 17+ CD8+ T cell subpopulation. Sequence analysis of 38 M58-66-specific V beta 17 transcripts from 13 subjects revealed extensive conservation in the CDR3 region including conservation of an arginine-serine motif. To test the dependence of this CTL response on the V beta 17 gene segment, peripheral blood lymphocytes were depleted of CD8+ TCR V beta 17+ cells, before the generation of M58-66-specific CTL. In most cases such depletion blocked or severely reduced the generation of the M58-66-specific response, and under limiting dilution conditions could abolish M58-66-specific CTL precursors. These studies reveal the dependence of this natural human immune response on a particular TCR gene segment.

scholarly journals Influenza A Virus-Specific H-2dRestricted Cross-Reactive Cytotoxic T Lymphocyte Epitope(s) Detected in the Hemagglutinin HA2 Subunit of A/Udorn/72

Virology ◽  
1995 ◽  
Vol 214 (2) ◽  
pp. 445-452 ◽  
Author(s):  
KAMAL U. SAIKH ◽  
JOHN D. MARTIN ◽  
A.H. NISHIKAWA ◽  
SUSAN B. DILLON
Keyword(s):  
Influenza A Virus ◽  
T Lymphocyte ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte

scholarly journals Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex.

1991 ◽  
Vol 173 (4) ◽  
pp. 1007-1015 ◽  
Author(s):  
A Vitiello ◽  
D Marchesini ◽  
J Furze ◽  
L A Sherman ◽  
R W Chesnut
Keyword(s):  
Transgenic Mice ◽  
T Lymphocyte ◽  
Matrix Protein ◽  
Cytotoxic T Lymphocyte ◽  
Dominant Role ◽  
Class I ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Restriction Element ◽  
Hla A2.1

Transgenic murine lines have been constructed that express a chimeric class I molecule composed of the alpha 1 and alpha 2 domains of HLA-A2.1 and the alpha 3, transmembrane, and cytoplasmic domains of H-2Kb. Upon immunization with influenza virus, transgenic mice developed a strong A2.1Kb-restricted cytotoxic T lymphocyte (CTL) response specific for the same matrix protein epitope that serves as the dominant A2.1-restricted determinant in the equivalent human response. Fine specificity analysis of CTL clones using truncated peptides revealed strong similarity between the response repertoire of transgenic mice and that previously reported using influenza-specific A2.1-restricted CTL clones from humans. This suggests that even when considering T cell responses by different species, the alpha 1 and alpha 2 domains of the restriction element play a dominant role in determining the CTL specific repertoire. Thus, substituting the alpha 3 domain of A2.1 with a murine counterpart has permitted development of a transgenic strain that should serve as an excellent model system in studies of HLA-restricted responses.

scholarly journals Structural Definition of Duck Major Histocompatibility Complex Class I Molecules That Might Explain Efficient Cytotoxic T Lymphocyte Immunity to Influenza A Virus

2017 ◽  
Vol 91 (14) ◽  
Author(s):  
Yanan Wu ◽  
Junya Wang ◽  
Shuhua Fan ◽  
Rong Chen ◽  
Yanjie Liu ◽  
...  
Keyword(s):  
Influenza A Virus ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Peptide Binding ◽  
Class I ◽  
Binding Motif ◽  
Mhc I ◽  
Peptide Binding Groove ◽  
Peptide Binding Motif ◽  
Binding Groove

ABSTRACT A single dominantly expressed allele of major histocompatibility complex class I (MHC I) may be responsible for the duck's high tolerance to highly pathogenic influenza A virus (HP-IAV) compared to the chicken's lower tolerance. In this study, the crystal structures of duck MHC I (Anpl-UAA*01) and duck β2-microglobulin (β2m) with two peptides from the H5N1 strains were determined. Two remarkable features were found to distinguish the Anpl-UAA*01 complex from other known MHC I structures. A disulfide bond formed by Cys95 and Cys112 and connecting the β5 and β6 sheets at the bottom of peptide binding groove (PBG) in Anpl-UAA*01 complex, which can enhance IAV peptide binding, was identified. Moreover, the interface area between duck MHC I and β2m was found to be larger than in other species. In addition, the two IAV peptides that display distinctive conformations in the PBG, B, and F pockets act as the primary anchor sites. Thirty-one IAV peptides were used to verify the peptide binding motif of Anpl-UAA*01, and the results confirmed that the peptide binding motif is similar to that of HLA-A*0201. Based on this motif, approximately 600 peptides from the IAV strains were partially verified as the candidate epitope peptides for Anpl-UAA*01, which is a far greater number than those for chicken BF2*2101 and BF2*0401 molecules. Extensive IAV peptide binding should allow for ducks with this Anpl-UAA*01 haplotype to resist IAV infection. IMPORTANCE Ducks are natural reservoirs of influenza A virus (IAV) and are more resistant to the IAV than chickens. Both ducks and chickens express only one dominant MHC I locus providing resistance to the virus. To investigate how MHC I provides IAV resistance, crystal structures of the dominantly expressed duck MHC class I (pAnpl-UAA*01) with two IAV peptides were determined. A disulfide bond was identified in the peptide binding groove that can facilitate Anpl-UAA*01 binding to IAV peptides. Anpl-UAA*01 has a much wider recognition spectrum of IAV epitope peptides than do chickens. The IAV peptides bound by Anpl-UAA*01 display distinctive conformations that can help induce an extensive cytotoxic T lymphocyte (CTL) response. In addition, the interface area between the duck MHC I and β2m is larger than in other species. These results indicate that HP-IAV resistance in ducks is due to extensive CTL responses induced by MHC I.

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