Early Control of Mycobacterium tuberculosis Infection Requiresil12rb1Expression byrag1-Dependent Lineages

Abstract

ABSTRACTIL12RB1is essential for human resistance toMycobacterium tuberculosisinfection. In the absence of a functionalIL12RB1allele, individuals exhibit susceptibility to disseminated, recurrent mycobacterial infections that are associated with defects in bothRAG1-dependent andRAG1-independent hematopoietic lineages. Despite this well-established association, a causal relationship betweenM. tuberculosissusceptibility andIL12RB1deficiency in eitherRAG1-dependent orRAG1-independent lineages has never been formally tested. Here, we use the low-dose aerosol model of experimental tuberculosis (TB) to both establish that infectedil12rb1−/−mice recapitulate important aspects of TB inIL12RB1null individuals and, more importantly, use radiation bone marrow chimeras to demonstrate that restriction ofil12rb1deficiency solely torag1-dependent lineages (i.e., T and B cells) allows for the full transfer of theil12rb1−/−phenotype. We further demonstrate that the protection afforded by adaptive lymphocyteil12rb1expression is mediated partially throughifngand that, within the same infection,il12rb1-sufficient T cells exhibit dominance overil12rb1-deficient T cells by enhancingifngexpression in the latter population. Collectively, our data establish a basic framework in which to understand howIL12RB1promotes control of this significant human disease.