A crucial role of the H-2 D locus in the regulation of both the D- and the K-associated cytotoxic T lymphocyte response against Moloney leukemia virus, demonstrated with two Db mutants.

Abstract Previous studies have shown that the CTL response of C57BL/6 (B6, H-2b) mice against Moloney leukemia virus is H-2 Db-restricted. In the current paper, we analyze the role of the H-2 Db locus in the CTL response against Moloney virus with two strains of mice carrying a mutation in the H-2 Db locus: Be-C-Hbm13 (bm13) and B6.C-H-2bm14 (bm14). The influence of the D locus was seen at two levels. First, neither of the two Db-mutant targets could be recognized by Db-restricted CTL, as demonstrated with B10.A(4R) (Kk Db) and B6 (Kb Db) effector cells. Second, mutation at the Db locus strongly altered the character of the response, either by causing nonresponsiveness (bm 14 effector) or by increasing the Kb-associated component of the CTL response (bm13 effector). These findings indicate that a single genetic element, H-2 D in this instance, determines the restriction specificity and regulates the magnitude of the CTL response. Cold target inhibition studies showed that either the restriction specificities of Dbm13 and Kb in the CTL response to this virus are indistinguishable or that the Dbm13-associated component of bm13 CTL is negligible. Experiments with (B6 × bm13)F1 and (B6 × bm14)F1 hybrid responding cells demonstrated a decisive role of H-2 on the antigen-presenting cells used for restimulation in vitro: primed F1 responding cells mounted CTL responses with the H-2 preference and magnitude of the parental cell type used for restimulation in vitro. Our findings strongly support the notion that type I MHC molecules regulate the magnitude and specificity of the CTL response against viruses.