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Virus-immune cytotoxic T cells recognize structural differences between serologically indistinguishable HLA-A2

W E Biddison, M S Krangel, J L Strominger

    Human Immunology
    |October 1, 1980
    PubMed
    Summary

    Human cytotoxic T cells recognize a specific self-determinant on HLA-A2 molecules, distinct from the serologically defined HLA-A2 antigen. This suggests multiple functional epitopes exist on the same HLA molecule.

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    Area of Science:

    • Immunology
    • Human Leukocyte Antigens (HLA)
    • T cell recognition

    Background:

    • Cytotoxic T lymphocytes (CTLs) play a crucial role in viral immunity by recognizing viral antigens presented by self-major histocompatibility complex (MHC) molecules.
    • The specificity of T cell recognition is determined by the interaction between the T cell receptor (TCR) and the peptide-MHC complex on target cells.
    • Human Leukocyte Antigen (HLA) molecules, particularly HLA class I (HLA-A, -B, -C), present viral peptides to CD8+ T cells.

    Purpose of the Study:

    • To investigate the relationship between self-determinants recognized by influenza virus-immune cytotoxic T cells and serologically defined HLA-A and HLA-B antigenic determinants.
    • To determine if structural variations within a specific HLA molecule can lead to differential T cell recognition.
    • To explore the concept of distinct epitopes on HLA molecules recognized by T cells versus antibodies.

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    Main Methods:

    • Generation of influenza virus-immune cytotoxic T cells in vitro from peripheral blood lymphocytes of healthy adult donors.
    • Testing of virus-immune T cells against a panel of virus-infected target cells from HLA-A2 positive donors, including HLA-mismatched and HLA-A2 matched individuals.
    • Serological analysis and isoelectric focusing of HLA-A2 molecules to identify structural differences in the M7 donor's A2 antigen.

    Main Results:

    • Virus-immune T cells from all tested HLA-A2 positive donors lysed A2-matched, virus-infected target cells, but consistently failed to lyse target cells from one specific A2-positive donor (M7).
    • While alloimmune T cells could distinguish the M7 A2 antigen, extensive serological analyses could not identify differences in the M7 A2 antigen.
    • Isoelectric focusing revealed that the M7 A2 heavy-polypeptide chain is structurally distinct from that of other A2 donors, indicating a molecular difference not detectable by standard serology.

    Conclusions:

    • There is a strong, yet incomplete, association between the self-antigen recognized by virus-immune T cells and the serologically defined HLA-A2 specificity.
    • The findings suggest the existence of at least two distinct epitopes on the same HLA-A2 molecule: one recognized by antibodies (serologically defined determinant) and another recognized by T cells (self-determinant).
    • Structural heterogeneity within HLA molecules, even within the same serological type, can significantly impact T cell recognition and self-specificity.