Effects of different environments and microbial exposures on the adult immune system of the C57BL/6 laboratory mouse strain

The realization that the grossly underdeveloped immune system of laboratory mice may hinder their use as suitable models of human disease has led to the development of different strategies to "normalize" immune responses in these mice so that they more closely resemble those typical of the human population. In this study, we performed a comprehensive comparison of the adult immune systems and microbiomes of C57BL/6 laboratory mice exposed to different housing and microbial conditions. C57/BL6 mice housed in a facility of substandard health levels (herein termed "dirty") and C57BL/6 mice born after embryo transfer from females captured in the field ("wildings") were compared to C57BL/6 mice housed under standard SPF laboratory conditions. Microbiota and parasite burden varied widely between the three conditions, which also showed marked differences among populations of mature, antigen-experienced, memory, plasma, and germinal centre B cells. Interestingly, we observed discrepancies among T cell phenotypes, with antigen-experienced T cells present at higher frequencies in "dirty" mice. On the other hand, "wildlings" displayed significantly elevated frequencies of both naive and antigen-experienced spleen T cells. Interestingly, "dirty" and "wildlings" showed differences in the expansion of distinct myeloid cell types. Lastly, we observed that systemic immune traits reverted to a "cleaner" profile in the progenies (F2) of "wildlings" raised under laboratory conditions, indicating that such mice may not be suitable for human immune system modelling after prolonged housing in laboratory environments. Collectively, our results highlight the profound effects of varied microbial exposures and husbandry conditions on adult immunity of the common C57BL/6 laboratory mouse and suggest that complex microbial exposure in laboratory mice can provide a relevant tool for modelling immunological functions, thus enhancing their translational value.