Cytotoxic T cells learn specificity for self H-2 during differentiation in the thymus

CELL mediated immune reactions in mice involving cytotoxic thymus derived lymphocytes have two important features; they are antigen-specific¹ and the structures coded for by the major murine histocompatibility gene complex (H-2) play an important part in killer cell-target cell interaction ¹. This finding is not unique to mice since it has also been reported for rats, humans and chickens^2-4. Two hypotheses have been suggested to explain this dual specificity of T killer cells; one proposes that T killer cells possess two separate structures, one of which recognises self H-2 structures and the other a non-H-2 antigen (dual recognition). The other hypothesis proposes that T killer cells possess one receptor which recognises an H-2 antigen modified by a non-H-2 antigen (modified self)^1,5. Evidence to test these hypotheses was sought by preparing chimaeras made by reconstituting lethally irradiated F₁ mice with bone marrow stem cells of one parent (Parent→F) refs 6-8) or neonatally tolerant mice ⁹ (mice of a parental H-2 type injected with F₁ cells as neonates). As a result, Parent → F₁ chimaeric lymphocytes lysed infected and trinitrophenyl (TNP)-modified targets of both parental H-2 types, suggesting that H-2 antigens of the killer cells were not involved in the lytic interaction. In contrast, lymphocytes from neonatally tolerant mice did not lyse infected targets from the incompatible parent⁹. Although these results can be explained by postulating a single receptor, they also fit the dual recognition hypothesis^6-10. Bevan has shown that irradiated bone marrow chimaeras of the type (A × B)F₁ → Parental A recipient generated preferentially cytotoxic T cells against minor histocompatibility antigens in association with the H-2 haplotype of the recipient A; he concluded that the chimaeric host determines the specificity of T cell restriction either through a thymic selection process as proposed by Jerne or alternatively through an antigen presentation mechanism.