Ir-genes in H-2 regulate generation of anti-viral cytotoxic T cells. Mapping to K or D and dominance of unresponsiveness.

Abstract

H-2 dependent and virus-specific Ir genes regulate the generation of primary virus-specific K or D restricted cytotoxic T-cell responses in vivo. The following examples have been analyzed in some detail: first, Dk restricted responses to vaccinia in Sendai viruses are at least 30 times lower than the corresponding K-restricted responses irrespective of the H-2 haplotypes (k, b, d, dxs, dxq) of K and I regions; in contrast, LCMV infection generates high responses to Dk. These findings are consistent with but do not prove that this Ir gene maps to D. Second, Db restricted responses to vaccinia and Sendai viruses are high in strains possessing the Kq or KbIb, KbaIb haplotype, are very low in strains with Kk, and relatively low in mouse strains of the KdI-Ad haplotype; LCMV generates high Db restricted response in the presence of Kk. This Ir gene for the response to vaccinia and Sendai viruses maps to K since B10.BYR (KqIkdDb) is a responder and B10.A (2R) is a nonresponder (KkIkdDb). Third, virus and K or D allele specific nonresponsiveness is dominant with variable penetrance; in heterozygous mice the nonresponder Kk allele over-rides responsiveness normally found in KbDb or KqDb combinations. Fourth, when (responder X nonresponder)F1 lymphocytes are stimulated in an environment expressing vaccinia virus plus only a high responder Kb or Kq allelle and Db, response to vaccinia Db is high; in contrast when the same F1 cells are stimulated in an environment expressing the low responder allele Kk, response to vaccinia Db is low. Thus absence of Kk during immunization allows generation of high responsive Db restricted vaccinia specific cytotoxic T cells. The Dk dependent low response to vaccinia Dk can be explained by a preclusion rule or by failure of vaccinia to complex with Db; however the analysis of Kk dependent low response to vaccinia Db does not support these explanations or that self-tolerance is responsible for this Ir effect but is compatible with the interpretation that Kk vaccinia is immunodominant over Db vaccinia. These results are discussed with respect to (a) possible mechanisms of regulation by Ir genes and (b) H-2 polymorphism and HLA-disease association.

Distinct Ir genes for helper and killer cells in the cytotoxic response to H-Y antigen.

“…We have shown that preference of H-Y-specific CTL for H-2 k occurs also in B6 --~ B6 X CBA chimeras, i.e., that the radioresistant tissue of the chimeric hosts influences the preference of H-Y-specific CTL for certain H-2 alleles (14). Similar observations on allele preference of virus-specific CTL have been made by Zinkernagel et al (15,16), Doherty et al (17), and Kurrle et al (18). In the response to vaccinia virus, no CTL restricted to D k could ever be demonstrated.…”

Regulation of T-cell-mediated lympholysis by the murine major histocompatibility complex. II. Control of cytotoxic responses to trinitrophenyl-K and -D self products by H-2K- and H-2D-Region genes.

“…Our findings are similar to those reported for CTL responses against vaccinia and Sendai virus (12). It was suggested that the failure to generate CML responses against vaccinia and Sendai virus recognized in association with D k self products may be attributable to/r genes mapping to the H-2D region (12).…”

“…These observations can be accounted for by at least two models. It is possible that certain genes (lr genes) for CML that are distinct from the structural genes coding for self-recognition products map within the K and D regions (12). Alternatively, it is possible that the lack of or magnitude of a CTL response is primarily attributable to the antigenic properties of each particular K-and D-region-coded molecule.…”

“…The introduction of k alleles throughout the I region did not result in ability to respond to low-dose TNP in association with H-2K b products. It should be noted that the preference of K k over D a self products in CML responses to vaccinia virus (12) as well as to TNP-self (11) have been mapped to the left of I-A, presumably to the K region. The results of the present study, which would appear to involve a different /r-like CML function, i.e., ability to respond to low-dose TNP-self, is also associated with the k haplotype and requires k alleles in the K region.…”

“…It was suggested that the failure to generate CML responses against vaccinia and Sendai virus recognized in association with D k self products may be attributable to/r genes mapping to the H-2D region (12).…”