CTL target cells

Following the demonstration of the requirements for MHC compatibility for macrophage/T lymphocyte interaction and for T lymphocyte/B lymphocyte interaction, it was shown by Zinkernagel and Doherty for virus-infected cells, by Shearer for targets modified with the TNP (trinitrophenyl) hapten, and by Bevan for targets bearing minor histocompatibility antigens, that the killing of antigen-bearing target cells by CD8+ T cells was also restricted by MHC antigens. In the virus studies, mice were infected with live virus and 7 days later their spleen cells were tested for their ability to kill virus-infected macrophages of the same or an allogeneic strain. T Cells derived from a virus-primed mouse would only kill target cells from the same strain and not allogeneic strains. In contrast to the results of studies with CD4+ helper or proliferating T cell populations, the restriction on the interaction of CD8+ CTLs with antigen-bearing target cells was mediated by the products of the K and D regions of the H2 complex (MHC class I antigens).

One of the original interpretations for the MHC restriction of macrophage/T lymphocyte and T/B lymphocyte interaction was that the interacting cells had to share a particular gene product (cell interaction model). This model was based on the idea that the interactions of immunocompetent cells involved like-like interactions and that the recognition of the specific antigen by the T cell receptor was independent of the molecules mediating cell-cell interaction. The results of their studies on the role of the MHC in restricting the interaction of CTLs with virus-infected targets led Zinkernagel and Doherty to propose an alternative model which stated that the antigen-specific T cell receptor was not specific for antigen, but recognized either modifications in the MHC class I antigens induced by viral proteins during the process of virus infection (altered self model) or that the nominal antigen formed a complex with the MHC antigens that was recognized as a unique antigen by the T cell receptor (complex antigenic determinant model).

Studies with T cells from F1 animals formed the basis of support for these models which required the associative recognition of the nominal antigen and the MHC antigen. Thus, if F1 animals were immun* ized with a virus, the resultant virus-specific population of CTLs would lyse targets from either of the parental strains. However, if F1 T cells from a virally infected animal were transferred to one of the parental strains which was then infected with the virus, the resultant restimulated CTL population would only lyse target cells derived from the parental strain in which the T cells were boosted.

This experimental result is very difficult to reconcile with the cell interaction model, which states that a single F1 T cell would bear cell interaction molecules of both parental types and should, following boosting in one or the other parental strain environments, be capable of recognizing virus-infected targets derived from either parental strain. A much more likely explanation is that the FIT cell population is composed of two distinct subpopulations, one of which is specific for viral determinants in association with MHC antigens of one parent, while the second is specific for viral determinants in association with MHC antigens from the other parent. Later studies demonstrated that CD4+ proliferating and helper T cells from F1 animals could also be divided into two distinct populations which were restricted in their interactions with macrophages or with B lymphocytes from one of the other parental strains, respectively.

The 1996 Nobel Prize in Physiology or Medicine was awarded to Peter Doherty and Rolf Zinkernagel 'for their discoveries concerning the specificity of the cell mediated immune defence'. These cellular studies formed the basis for the biochemical and molecular dissection of the polymorphism of MHC antigens which directly demonstrated that peptides derived from antigens are bound by the polymorphic regions of the MHC antigens and then displayed to the T cell receptor as a complex in the context of exposed sites on the a helices of the MHC molecules.

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