Abstract. Why 5-10% of people develop tuberculosis (TB) after Mycobacterium tuberculosis (Mtb) infection is largely unknown. Th1 immunity is the dominant mechanism of control. In contrast, how type 2 immunity affects immunity to TB is a clinically important area that has scarcely been investigated. Th2 immune responses are elicited by helminths parasites, and concurrent helminth and Mtb infection are a real concern. Half of the 180 million school age children in Sub-Saharan Africa are estimated to be infected with helminths. Chronic helminth infection induces Th2 and Tregs, both which inhibit Th1 immunity, and impair BCG efficacy. IL-4, IL-5, and IL-13 are the canonical cytokines of Th2 cells. These cytokines are also produced by other cells including eosinophils and mast cells. We discovered that BCG vaccination worsens subsequent Mtb infection in CC040 mice and is associated with the emergence of IL-4-producing cells in the lung. Our overarching hypothesis is that IL-4 production in CC040 mice permits Mtb growth and exacerbates disease in BCG vaccinated mice. Mtb causes more than 10 million cases of TB and 1.5 million deaths each year. To halt the spread of TB, including drug resistant Mtb strains, a safe and effective vaccine is needed. BCG, an attenuated derivative of the related M. bovis species, has been used as a vaccine against TB in billions of people in more than 180 countries. BCG prevents disseminated TB in infants but estimates of protection against pulmonary TB range from 75% to none in several populations in endemic regions. While the mouse has been outstanding in developing immunological concepts that translate into humans, standard inbred strains lack the genetic diversity of people. Th1 immunity develops following Mtb infection in C57BL/6 (B6) mice, which is the “go to” strain for immunologists. However, B6 mice inadequately model other immune responses including Th2 and Th17 responses, and MAIT cells. To address the shortcomings of the murine TB model, we are using Collaborative Cross (CC) mice to study TB pathogenesis and mechanisms of vaccine-induced immunity. CC mice were developed from eight parental strains that included wild-derived mice. The breeding schemes captured >90% of the diversity present in the Musspecies and led to the creation of ~70 CC strains. The CC040 strain is one such strain in which we detected a clinically relevant phenotype – one that may have been obscured by over-reliance on traditional mouse models (i.e., B6). Using the CC040 mouse strain, we will ask how IL-4, and the cells producing IL-4, modify immunity to TB. We will compare immunity in CC040 and B6 control mice to determine how IL-4 affects vaccine-induced protection against Mtb infection. New insights into how mast cells and eosinophils affect TB susceptibility are changing the way we view immunity to mycobacteria. We expect that the CC040 strain will be an important tool to understand how IL-4 and IL-4 producing cells affect immunity to Mtb. Given the central role of eosinophils and mast cells in the pathogenesis of other pulmonary diseases, we expect that CC040 mice will be useful to the broader scientific community for in vivo research into the regulation and manipulation of IL-4.