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Immune homeostasis is the state that the immune system maintains in the absence of insult. Perturbation of immune homeostasis can impact autoimmunity/allergy and adversely affect infectious responses. To date, much of the analysis of immune homeostasis has focused on systemic immunity, but it is also likely to be important in an organ specific manner. Since the lungs are a major site of environmental exposure and infection, we used the Collaborative Cross (CC) mouse genetic reference population to study the genetic regulation of the breadth of baseline immune cell populations in the lung and identify loci regulating these cells at homeostasis. We found that all 54 immune cell phenotypes measured showed strong genetic variation in cell type abundances. We identified 28 quantitative trait loci associated with variation in 24 immune cell populations or the relationship between cell populations. Further, we identified significant associations between 20 of these loci and responses to either influenza A virus (IAV) or Severe acute respiratory syndrome associated coronavirus (SARS-CoV) disease in the same strains of mice. Notably, a locus mapped for variation in Ly6C+ monocyte abundance was associated with SARS-CoV weight loss, as well as titer at days 2 and 4 post-infection. This locus is also associated with influenza-induced disease, as measured by weight loss post-infection. Our analysis highlights the strong genetic control of immune homeostasis, and the key role that immune homeostasis plays in contributing to downstream infectious responses. In particular, our analysis suggests that the abundance of a variety of lung leukocyte populations prior to infection could serve as predictors of immune responses to respiratory viruses.

Background: The development of peanut allergy is due to a combination of genetic and environmental factors, although specific genes have proven difficult to identify. Previously, we reported that peanut-sensitized CC027/GeniUnc (CC027) mice develop anaphylaxis upon oral challenge to peanut, unlike C3H/HeJ (C3H) mice., Objective: To determine the genetic basis of orally-induced anaphylaxis to peanut in CC027 mice., Methods: A genetic mapping population between CC027 and C3H mice was designed to identify the genetic factors that drive oral anaphylaxis. A total of 356 CC027xC3H backcrossed mice were generated, sensitized to peanut, then challenged to peanut by oral gavage. Anaphylaxis and peanut-specific IgE were quantified for all mice. T-cell phenotyping was conducted on CC027 and five additional CC strains., Results: Anaphylaxis to peanut was absent in 77% of backcrossed mice, with 19% showing moderate anaphylaxis, and 4% having severe anaphylaxis. A total of eight genetic loci were associated with variation in response to peanut challenge, six associated with anaphylaxis (temperature decrease) and two associated with peanut-specific IgE levels. There were two major loci that impacted multiple aspects of the severity of acute anaphylaxis, at which the CC027 allele was associated with worse outcome. At one of these loci, CC027 has a private genetic variant in the Themis (thymocyte-expressed molecule involved in selection) gene. Consistent with Themis' described functions, we found that CC027 have more immature T cells with fewer CD8+, CD4+, and CD4+CD25+CD127- regulatory T cells., Conclusion: Our results demonstrate a key role for Themis in the orally-reactive CC027 mouse model of peanut allergy.