Marrow-reconstituted Mice In

Products of the major histocompatibility complex (MHC) 1 play an important role in the recognition of antigen by cytolytic T lymphocytes (CTL). Viral (1) and minor histocompatibility antigens (2) or chemical modifiers (3) are recognized by C T L in association with H-2 antigens. The H-2 environment in which T cells mature, and not their genotype, determines the H-2 restriction of C T L (4, 5). This was shown by radiation bone marrow chimeras, where an A stem cell matures in an (A × B)F1 environment and, thus, recognizes antigen in association with H-2 A or H-2 B. (A × B)Fa stem cells maturing in a parental environment (A) will only recognize antigen in association with H-2 A. Initially, most data suggested (5-7) that it was the H-2 environment of the thymus that determined the specificity of the CTL repertoire. Recently, several sets of experiments suggest that the extrathymic environment can also play a role in the maturation and ultimate specificity of CTL: (a) nude mice that only possess a thymic rudiment (8) could generate CTL both in vitro (9-11) and in vivo (12) when interleukin 2 (IL-2) was provided; (b) in nude mice grafted with a thymus, the thymus determined the H-2 restriction when (A × B)Fa nude mice were grafted with a parental thymus, but in parental nude mice grafted with an allogeneic thymus (13) or an F1 thymus (14), the parental nude environment determines the restriction; (c) Kruisbeek et al. (15) have shown that the extrathymic environment seems to play a role in the 1-I-2 restriction of splenic C T L but not thymic C T L in thymus-engrafted nude mice. There is some concern that the nude mouse is a poor model for studying extrathymic T cell differentiation because it may have other genetic defects that may influence the ultimate CTL repertoire. This concern stimulated us to develop a better defined model system for studying extrathymic T cell differentiation. I f nude mice represent a model where stem cells have been able to differentiate without a thymic influence, we would expect that C T L should be generated in thymectomized, irradiated, and bone marrow-reconstituted chimeras. Previous experiments (16) have not shown the generation of CTL in such animals unless they were reconstituted with bone marrowcontaining mature T cells. We hypothesized that in such animals, as in nude mice,