Viral Infection Skews Immunoglobulin Light Chain Repertoire Diversity

Abstract

Antibody responses are fundamentally important to effector and memory mechanisms of disease resistance. Antibody repertoire diversity and its response to natural infection is poorly understood, yet is a prerequisite for molecular and structural elucidation of functionally protective immunity to viral infections. Using a swine model of mammalian viral infection, we observed marked changes following infection with the major porcine pathogen, porcine reproductive and respiratory syndrome virus (PRRSV). Deep sequencing of >516,000 light chain VJ mRNA genes showed that, similar to humans, swine utilize both lambda and kappa loci equivalently. However, V and J gene usage were highly restricted; [≥]99% of lambda light chains were IGLV3 and IGLV8 family members joined to IGLJ2 or IGLJ3, and 100% of kappa locus transcripts were IGKV1 or IGKV2 with only IGKJ2. Complementarity-determining region (CDR) variation was limited. Nevertheless, total diversity richness estimates were 2.3 x 105 for lambda and 1.5 x 105 for kappa, due in part to extensive germline variation in framework regions and allelic variation. Infection by PRRSV reduced total richness due to expression of several highly abundant clonal populations. Antibody light chain repertoires differed substantially among individuals, thus illustrating extensive potential variation in immune response in outbred populations. These findings demonstrate that individual variation in light chain repertoires may be an important component of variable antibody responses to infection and vaccination, and that swine are a relevant model of human antibody diversification in which the immune response capacity is critical to understanding individual variation in immune protection against disease.\n\nConflict of interest statementThe authors declare no conflicts of interest.\n\nHighlightsO_LI{lambda} and {kappa} light chain diversity is equivalent to heavy chain diversity\nC_LIO_LIHigh diversity is present despite limited gene segment usage\nC_LIO_LIPRRSV infection increases abundance of dominant {lambda} and {kappa} VJ clones\nC_LIO_LIHigh levels of variation are present among animals\nC_LI