The present study was performed to examine the specificity of the self-recognition repertoire expressed by TNP-specific CTL precursors present in the thymus and the spleen of congenitally athymic nude mice engrafted with either semiallogeneic or fully allogeneic neonatal thymuses. It was shown that the engrafted thymus lobes were fully repopulated with cells of nude host origin and that the engrafted thymus tissue was capable of reconstituting peripheral CTL function in the nude host. Assessing the specificity of the lymphocytes differentiating within the thymus graft, the present study revealed that CTL precursors of nude host origin in the thymus grafts were nonalloreactive to both nude-host-type and thymus-type MHC determinants but were invariably restricted to the self-recognition of thymus-type, not nude-host-type, MHC determinants. Furthermore, the restricted self-recognition of thymic MHC determinants was not mediated by detectable suppression. In contrast to the restricted self-recognition repertoire of CTL precursors in the thymus of these mice, CTL precursors from the spleens of the same mice were not restricted to the self-recognition of thymus-type MHC determinants but instead recognized TNP in association with both host and thymus-type MHC determinants. These data demonstrate that at least in thymus-engrafted nude mice the self-recognition repertoire of thymocyte CTL, but not spleen CTL, is entirely dictated by the MHC phenotype of the thymus tissue in which they differentiate. It is proposed that the spleen CTL repertoire in these mice reflects the coexistence of at least 2 CTL subpopulations, 1 that differentiated within the engrafted thymus and 1 that differentiated outside the engrafted thymus.