Prevalent de novo somatic mutations in superantigen genes of mouse mammary tumor viruses in the genome of C57BL/6J mice and its potential implication in the immune system

Abstract

BackgroundSuperantigens (SAgs) of mouse mammary tumor viruses (MMTVs) play a crucial role in T cell selection in the thymus in a T cell receptor (TCR) Vβ-specific manner and SAgs presented by B cells activate T cells in the periphery. The peripheral T cell repertoire is dynamically shaped by the steady induction of T cell tolerance against self antigens throughout the lifespan. We hypothesize that de novo somatic mutation of endogenous MMTV SAgs contributes to the modulation of the peripheral T cell repertoire.ResultsSAg coding sequences were cloned from the genomic DNAs and/or cDNAs of various tissues of female C57BL/6J mice. A total of 68 unique SAg sequences (54 translated sequences) were identified from the genomic DNAs of liver, lungs, and bone marrow, which are presumed to harbor only three endogenous MMTV loci (Mtv-8, Mtv-9, and Mtv-17). Similarly, 69 unique SAg sequences (58 translated sequences) were cloned from the cDNAs of 18 different tissues. Examination of putative TCR Vβ specificity suggested that some of the SAg isoforms identified in this study have Vβ specificities different from the reference SAgs of Mtv-8, Mtv-9, or Mtv-17.ConclusionThe pool of diverse SAg isoforms, generated by de novo somatic mutation, may play a role in the shaping of the peripheral T cell repertoire including the autoimmune T cell population.

Genomic landscapes of endogenous retroviruses unveil intricate genetics of conventional and genetically-engineered laboratory mouse strains

“…Our recent finding of highly polymorphic TRE profiles in the mouse population is inconsistent with the current assumption of high genome identity with regard to their conventional gene sequences (Frazer et al, 2007; Kao et al, 2012; Kirby et al, 2010; Lee et al, 2011; Mekada et al, 2009). In addition, recent findings of age- and organ-specific variations in genomic configurations due to TRE activity in C57BL/6J inbred mice contradicts the perceived genetic staticity and uniformity of a given inbred mouse population (Lee et al, 2012).…”

“…To evaluate whether polymorphisms in “TREome genes” cast potential impacts on variable phenotypes among the mouse population, we examined sequence diversity in MMTV-ERV SAg genes, a well-studied immune-regulatory TREome gene (Lee et al, 2011; Peters et al, 1983), among 57 laboratory mouse strains. Only 46 of the 57 mouse strains yielded visible MMTV-ERV LTR amplicons which are presumed to harbor the SAg gene open reading frame (ORF).…”