We have investigated elements of the genetic control of human in vitro cytotoxic T-cell responses to influenza virus-infected autologous cells by studies of a large family. The pattern of virus-immune cytotoxicity among siblings demonstrated T-cell recognition of influenza virus predominantly (greater than 90%) in association with determinants which are coded by genes linked to HLA (P less than 0.0002). Many family members consistently generated cytotoxic activity against influenza predominantly in association with antigens coded by genes of only one of their HLA haplotypes. Such haplotype preferences were consistent among HLA-identical siblings, indicating that the specificity of the T-cell response to influenza virus in association with HLA-A and -B antigens is controlled by genes linked to HLA.

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