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

Abstract

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 interaction¹. 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 mice⁹ (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.