Genetic regulation of homeostatic immune architecture in the lungs of Collaborative Cross mice

Hampton, Brea K.; Jensen, Kara L.; Whitmore, Alan C.; Linnertz, Colton L.; Maurizio, Paul; Miller, Darla R.; Morrison, Clayton R.; Noll, Kelsey E.; Plante, Kenneth S.; Shaw, Ginger D.; West, Ande; Baric, Ralph S.; de Villena, Fernando Pardo-Manuel; Heise, Mark T.; Ferris, Martin T.

Variation in immune homeostasis, immune system stability, in organ systems such as the lungs is likely to shape the host response to infection at these exposed tissues. We evaluated immune homeostasis in immune cell populations in the lungs of the Collaborative Cross (CC) mouse genetic reference population. We found vast heritable variation in leukocyte populations with the frequency of many of these cell types showing distinct patterns relative to classic inbred strains C57BL/6J and BALB/cJ. We identified 28 quantitative trait loci (QTL) associated with variation in baseline lung immune cell populations, including several loci that broadly regulate the abundance of immune populations from distinct developmental lineages, and found that many of these loci have predictive value for influenza disease outcomes, demonstrating that genetic determinants of homeostatic immunity in the lungs regulate susceptibility to virus-induced disease. All told, we highlight the need to assess diverse mouse strains in understanding immune homeostasis and resulting immune responses.