IL12Rβ1ΔTM Is a Secreted Product of il12rb1That Promotes Control of Extrapulmonary Tuberculosis

ABSTRACTIL12RB1is a human gene that is important for resistance to Mycobacterium tuberculosisinfection. IL12RB1is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12Rβ1) that associates with IL12p40 and promotes the development of host-protective TH1cells. Recently, we observed that il12rb1—the mouse homolog of IL12RB1—is alternatively spliced by leukocytes to produce a second isoform (IL12Rβ1ΔTM) that has biological properties distinct from IL12Rβ1. Although the expression of IL12Rβ1ΔTM is elicited by M. tuberculosisin vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12Rβ1ΔTM to controlling M. tuberculosisinfection has not been tested. Here, we demonstrate that IL12Rβ1ΔTM represents a secreted product of il12rb1that, when absent from mice, compromises their ability to control M. tuberculosisinfection in extrapulmonary organs. Furthermore, elevated M. tuberculosisburdens in IL12Rβ1ΔTM-deficient animals are associated with decreased lymph node cellularity and a decline in TH1 development. Collectively, these data support a model wherein IL12Rβ1ΔTM is a secreted product of il12rb1that promotes resistance to M. tuberculosisinfection by potentiating THcells response to IL-12.