IntroductionTo dissect the role of the part of theH2complex comprised of the MHC-II genes in the control of tuberculosis (TB) infection, we previously established a panel of recombinant congenic mouse strains bearing different segments of theH2jhaplotype on the B6 (H2b) genetic background. Fine genetic mapping, gene sequencing and assessment of TB phenotypes resulted in identification of theH2-Abgene as a major factor of TB control.MethodsWe further narrowed the MHC-IIH2jinterval by spotting a new recombination event, sequencing newly established DNA configuration and establishing a mouse strain B6.I-103 in whichj/brecombination occurred within the coding sequence of theH2-Abgene.ResultsUnexpectedly, a novelH2-Aαb/AβjE0haplotype 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/Aβjmolecule 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.DiscussionOur findings provide evidence that Class II α/β-chaincis-allelic mismatches created by regular genetic recombination may severely affect immune system functioning. This issue is discussed in the context of the MHC evolution.