Discussion
Our findings provide evidence that Class II α/β-chain cis-allelic mismatches created by regular genetic recombination may severely affect immune system functioning. This issue is discussed in the context of the MHC evolution.
Methods
We further narrowed the MHC-II H2 j interval by spotting a new recombination event, sequencing newly established DNA configuration and establishing a mouse strain B6.I-103 in which j/b recombination occurred within the coding sequence of the H2-Ab gene.
Results
Unexpectedly, a novel H2-Aα b/AβjE0 haplotype provided exclusively high susceptibility to TB challenge. Immunologic analysis revealed an altered CD4+ T-cell selection and maintenance in B6.I-103 mice, as well as seriously impaired expression of the H2-Aαb/Aβj molecule on the surface of antigen presenting cells. Unlike previously reported cases of Class II malfunctioning, the defective phenotype arose not from strong structural mutations, but from regular recombination events within the MHC-II recombination hot spot region.