Combinatorial immunological light chain variability creates sufficient B cell diversity to mount protective antibody responses against pathogen infections

Abstract

To analyze how combinatorial light (L) chain diversity influences the B cell repertoire, we studied mice with a homozygous immunoglobulin-heavy-chain null mutation (μMT), in which the B cell developmental block was overridden by the expression of a transgenic immunoglobulin μ heavy (H) chain derived from a vesicular stomatitis virus Indiana serotype (VSV-ND)-neutralizing Ab (T11 μMT mice). The randomly integrated transgene could not undergo secondary rearrangements and was expressed in combination with endogenous κ or λ chains. T11μMT mice had a skewed B cell repertoire as evidenced by 30-60% VSV-IND-specific peripheral B cells and spontaneous VSV-IND-neutralizing serum titers. Upon immunization, T11μMT mice mounted specific IgM antibody responses against VSV-IND but, interestingly, they also responded against VSV New Jersey serotype (VSV-NJ), lymphocytic choriomeningitis virus, poliovirus and Salmonella typhi porins. Variable-region sequence analysis revealed that VSV-NJ-specific antibodies expressed numerous L chains in combination with the transgenic H chain, which was devoid of hypermutations. Thus, in T11 μMT mice combinatorial L chain variability alone is able to build up a sufficiently complex B cell repertoire to mount protective immunoglobulin responses against a variety of pathogens.