Brief DeNnitlve Report IN IRRADIATION CHIMERAS, K OR D REGIONS OF T H E CHIMERIC HOST, NOT OF THE DONOR LYMPHOCYTES, DETERMINE IMMUNE RESPONSIVENESS OF ANTIVIRAL CYTOTOXIC T CELLS*

H-2-1inked lr genes, which regulate the virus-specific responsiveness of cytotoxic H2K or D restricted T cells, have the following characteristics: they are virusand H-2specific. They act on cytotoxic T cells directly, but probably not on conventional T helper cells, since in all mouse strains responsiveness restricted to either K or D is high. Low responsiveness is quantitative, not qualitative unresponsiveness, and it has dominant character; lr genes that regulate responsiveness ofcytotoxic K or D restricted T cells map either to the K or D region o f H-2 (1). Two general types of lr gene regulation have been studied: (a) the K k haplotype causes low, but the K ° and K q cause high cytotoxic T-cell responsiveness to D n plus vaccinia virus. This Ir effect can be best explained by the immunodominance o f a K krestricted response to vaccinia over a response to D b plus vaccinia. This explanation is compatible with the finding that nonresponder lymphocytes of KkD b mice respond well to D b plus vaccinia antigen if they are restimulated selectively in an immunogenic environment expresing D b plus vaccinia, but not in one expressing K k plus vaccinia. (b) Vaccinia virus-specific cytotoxic T-cell responses that are restricted to D k apparently cannot be generated, regardless of any tested K or I region alleles. Therefore, this lr gene seems to map to D. Low response may again reflect the fact that all the vaccinia responses restricted to all K or D alleles tested so far are immunodominant over the response to D k plus vaccinia. T h e s e / r effects can be explained in a dual recognition model of T-cell recognition either by a genetic exclusion mechanism at the level of the genes coding for T-cell receptor variable regions, or by tolerance (1, 2). However, it cannot be excluded t ha t / r effects may be expressed at the level of antigen presentation, determined by the capacity of viral antigen to "complex" more or less immunogenically with the restricting K or D structures (3, 4). These results and models are compatible with Ir effects regulating T-helper cells (4, 5), and T cells specific for the male H-Y antigen (6, 7). Recently we demonstrated that the restriction specificity of cytotoxic T cells was selected by the H-2K and D haplotype of the radioresistant portion of the thymus (8,