Preferential HLA Usage in the Influenza Virus-Specific CTL Response

Abstract

To study whether individual HLA class I alleles are used preferentially or equally in human virus-specific CTL responses, the contribution of individual HLA-A and -B alleles to the human influenza virus-specific CTL response was investigated. To this end, PBMC were obtained from three groups of HLA-A and -B identical blood donors and stimulated with influenza virus. In the virus-specific CD8+ T cell population, the proportion of IFN-γ- and TNF-α-producing cells, restricted by individual HLA-A and -B alleles, was determined using virus-infected C1R cells expressing a single HLA-A or -B allele for restimulation of these cells. In HLA-B*2705- and HLA-B*3501-positive individuals, these alleles were preferentially used in the influenza A virus-specific CTL response, while the contribution of HLA-B*0801 and HLA-A*0101 was minor in these donors. The magnitude of the HLA-B*0801-restricted response was even lower in the presence of HLA-B*2705. C1R cells expressing HLA-B*2705, HLA-A*0101, or HLA-A*0201 were preferentially lysed by virus-specific CD8+ T cells. In contrast, the CTL response to influenza B virus was mainly directed toward HLA-B*0801-restricted epitopes. Thus, the preferential use of HLA alleles depended on the virus studied.

HLA class I molecules consistently present internal influenza epitopes

“…In addition, influenza epitopes that elicit IFN-␥ or cytotoxic responses have been described for 7 HLA-B alleles (B*0702, B*08, B*14, B*27, B*3501, B*37, and B*44) as compared to only 5 HLA-A alleles with an average of 2.1 and 1.4 epitopes presented per HLA-B and HLA-A allele, respectively (9). HLA-B molecules therefore play an integral role in directing CTL responses to a number of viruses including HIV (10,11), EBV (11,12), and influenza (8,13).…”

“…Class I molecules sample the proteome of the infected cell and display on the cell surface short viral peptides [8][9][10][11][12] aa in length to surveying immune cells (1). Two factors have complicated our understanding of the class I HLA-presented epitopes that distinguish influenza-infected cells.…”

“…For viruses such as HIV and EBV it has been observed that class I molecules encoded at the HLA-B locus contribute heavily to anti-viral CTL immune responses, and HLA-B molecules appear key to influenza CTL immunity as well. For example, HLA-B*2705 and -B*3501 represent primary targets for influenza-specific CTL responses in comparison to HLA-A*0201 and -A*0101 restricted CTL responses (8). In addition, influenza epitopes that elicit IFN-␥ or cytotoxic responses have been described for 7 HLA-B alleles (B*0702, B*08, B*14, B*27, B*3501, B*37, and B*44) as compared to only 5 HLA-A alleles with an average of 2.1 and 1.4 epitopes presented per HLA-B and HLA-A allele, respectively (9).…”

Naturally processed and HLA‐B8‐presented HPV16 E7 epitope recognized by T cells from patients with cervical cancer

“…19 The cellular immune response directed against these pathogens appears to be exceptionally restricted due to either structural constraints imposed by the HLA-B8/peptide complex on T-cell receptor recognition, 20 -22 or, not mutually exclusive, preferential presentation of immunogenic peptides selected by individual MHC alleles. 19 We show in this report that HLA-B8 serves as the restricting element for a naturally processed and presented HPV16 E7 epitope and that T cells directed against this antigen are present in the peripheral circulation of patients with cervical cancer.…”

“…We have examined HLA-B8 as a restricting element for anti-HPV-directed immune responses, since HLA-B8 is one of the most frequent alleles in the local region and in the entire European Caucasian population, 18 the frequency of this allele appears to be enhanced in patients with preinvasive or invasive cervical cancer lesions, and it represents a restriction element in the context of other viral diseases, e.g., EBV, HIV, or influenza B. 19 The cellular immune response directed against these pathogens appears to be exceptionally restricted due to either structural constraints imposed by the HLA-B8/peptide complex on T-cell receptor recognition, 20 -22 or, not mutually exclusive, preferential presentation of immunogenic peptides selected by individual MHC alleles. 19 We show in this report that HLA-B8 serves as the restricting element for a naturally processed and presented HPV16 E7 epitope and that T cells directed against this antigen are present in the peripheral circulation of patients with cervical cancer.…”