Early control of Mycobacterium tuberculosis infection requires il12rb1 expression by rag1-dependent lineages

IL12RB1 is essential for human resistance to Mycobacterium tuberculosis infection. In the absence of a functional IL12RB1 allele, individuals exhibit susceptibility to disseminated, recurrent mycobacterial infections that are associated with defects in both RAG1-dependent and RAG1-independent hematopoietic lineages. Despite this well-established association, a causal relationship between M. tuberculosis susceptibility and IL12RB1 deficiency in either RAG1-dependent or RAG1-independent lineages has never been formally tested. Here, we use the low-dose aerosol model of experimental tuberculosis (TB) to both establish that infected il12rb1(-/-) mice recapitulate important aspects of TB in IL12RB1 null individuals and, more importantly, use radiation bone marrow chimeras to demonstrate that restriction of il12rb1 deficiency solely to rag1-dependent lineages (i.e., T and B cells) allows for the full transfer of the il12rb1(-/-) phenotype. We further demonstrate that the protection afforded by adaptive lymphocyte il12rb1 expression is mediated partially through ifng and that, within the same infection, il12rb1-sufficient T cells exhibit dominance over il12rb1-deficient T cells by enhancing ifng expression in the latter population. Collectively, our data establish a basic framework in which to understand how IL12RB1 promotes control of this significant human disease.