AKR/J gene(s) unlinked to H-2 determines dominant inheritance of lymphocyte hyporesponsiveness to acetylcholine receptor

Mice with the H-2(b) major histocompatibility complex haplotype are high immune responders to nicotinic acetylcholine receptors (AChR), whereas mice with the H-2(k) haplotype are generally low responders. F₁ progeny of C57BL/6 (H-2(b)) mice crossed with mice of most H-2(k) strains are high responders to AChR in standard conditions of testing helper T cell proliferation in vitro (4 x 10⁵ lymph node cells/microwell, 1 wk after primary challenge in vivo). In contrast, the F₁ progeny of AKR/J (H-2(k)) crossed with high responder (H-2(b)) strains (B6, A.BY, or C3H.SW) were all hyporesponsive to AChR when lymphocytes were tested at 4 x 10⁵ cells/well. However, at a density of 1 x 10⁶ or greater/well, a high level of antigen-specific responsiveness was demonstrable in the F₁ hybrid lymphocytes. A shift from low to high responsiveness to AChR at high cell densities was observed also in the H-2(b) strain AKR.B6. Other strains previously demonstrated to be low responders to AChR did not become responsive to AChR when lymphocyte numbers were increased to 1.4 x 10⁶/well. The N₂ generation yielded by backcrossing (AKR x B6)F₁ mice to AKR/J were all low responders, whereas N₂ progeny derived by backcrossing F₁ to B6 were high or low responders in a ratio of approximately 1:1 (independent of their H-2 phenotype). Results consistent with this observation were obtained in (AKR x B6) F₂ mice. These data suggest that at least one AKR/J gene outside of the H-2 complex exerts a hyporesponsive influence on the I-A-dependent helper T cell response to AChR in H-2(b) mice.