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Journal of Virology, January 2002, p. 582-590, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.582-590.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Magnitude and Specificity of Influenza A Virus-Specific Cytotoxic T-Lymphocyte Responses in Humans Is Related to HLA-A and -B Phenotype

A. C. M. Boon,1 G. de Mutsert,1 Y. M. F. Graus,2 R. A. M. Fouchier,1 K. Sintnicolaas,3 A. D. M. E. Osterhaus,1 and G. F. Rimmelzwaan1*

Institute of Virology, Erasmus University Rotterdam, 3015 GE Rotterdam,1 Numico Research B. V., 6700 CA Wageningen,2 Bloodbank Rotterdam, Laboratory for Histocompatibility and Immunogenetics, 3318 AS Dordrecht, The Netherlands3

Received 2 July 2001/ Accepted 15 October 2001

The repertoire of human cytotoxic T-lymphocytes (CTL) in response to influenza A viruses has been shown to be directed towards multiple epitopes, with a dominant response to the HLA-A2-restricted M158–66 epitope. These studies, however, were performed with peripheral blood mononuclear cells (PBMC) of individuals selected randomly with respect to HLA phenotype or selected for the expression of one HLA allele without considering an influence of other HLA molecules. In addition, little information is available on the influence of HLA makeup on the overall CTL response against influenza viruses. Here, the influenza A virus-specific CTL response was investigated in groups of HLA-A and -B identical individuals. Between groups the individuals shared two or three of the four HLA-A and -B alleles. After in vitro stimulation of PBMC with influenza virus, the highest CTL activity was found in HLA-A2+ donors. A similar pattern was observed for the precursor frequency of virus-specific CTL (CTLp) ex vivo, with a higher CTLp frequency in HLA-A2-positive donors than in HLA-A2-negative donors, which were unable to recognize the immunodominant M158–66 epitope. In addition, CTL activity and frequency of CTLp for the individual influenza virus epitopes were determined. The frequency of CTLp specific for the HLA-B8-restricted epitope NP380–388 was threefold lower in HLA-B27-positive donors than in HLA-B27-negative donors. In addition, the frequency of CTLp specific for the HLA-A1-restricted epitope NP44–52 was threefold higher in HLA-A1-, -A2-, -B8-, and -B35-positive donors than in other donors, which was confirmed by measuring the CTL activity in vitro. These findings indicate that the epitope specificity of the CTL response is related to the phenotype of the other HLA molecules. Furthermore, the magnitude of the influenza virus-specific CTL response seems dependent on the HLA-A and -B phenotypes.

* Corresponding author. Mailing address: Erasmus University Rotterdam, Institute of Virology, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. Phone: 010-4088066. Fax: 010-4089485. E-mail: rimmelzwaan{at}viro.fgg.eur.nl.

Journal of Virology, January 2002, p. 582-590, Vol. 76, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/JVI.76.2.582-590.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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