Antigen recognition by cloned cytotoxic T lymphocytes follows rules predicted by the altered-self hypothesis

Abstract

Radiation chimeras prepared by injecting H-2 heterozygous F1 stem cells into lethally irradiated parental hosts show a marked, but not absolute, preference for host-type H-2 antigens in the H-2-restricted cytotoxic T lymphocyte (CTL) response to minor histocompatibility (minor H) antigens. We have selected for the anti-minor H CTL that are restricted to the parental H-2 type absent from the chimeric host and found that in two out of eight cases, such CTL lysed target cells of either parental H-2 type. From one of these CTL populations that lysed H-2(d) and H-2(k) target cells expressing BALB minor H antigens, clones were derived and further analyzed. The results showed that: (a) lysis of both H-2(d) and H-2(k) target cells was H-2 restricted; (b) H-2(d) restriction mapped to D(d), and H-2(k) restriction mapped to K(k); (c) testing against various H-2(d) and H-2(k) strains of different and partially overlapping minor H backgrounds as well as against the appropriate F1 crosses revealed that in D(d)- and K(k)- restricted killing, different minor H antigens were recognized. In a second system, a CTL population was selected from normal (H-2(d) x H-2(k))F1 mice that was specific for H-2(d) plus minor H antigens and for H-2(k) plus trinitrophenylated bovine serum albumin. We interpret these findings in terms of the altered-self hypothesis: The association of one H-2 antigen with one conventional antigen X may be recognized by the same T cell receptor specific for the complex formed by a different H-2 antigen in association with a second conventional antigen Y. The implications of these observations for the influence of self H-2 on the generation of the T cell receptor repertoire are discussed.