title: IL12Rβ1ΔTM is a secreted product of il12rb1 that promotes control of extrapulmonary tuberculosis.
abstract: IL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12Rβ1) that associates with IL12p40 and promotes the development of host-protective T(H)1 cells. 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. tuberculosis in vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12Rβ1ΔTM to controlling M. tuberculosis infection has not been tested. Here, we demonstrate that IL12Rβ1ΔTM represents a secreted product of il12rb1 that, when absent from mice, compromises their ability to control M. tuberculosis infection in extrapulmonary organs. Furthermore, elevated M. tuberculosis burdens 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 il12rb1 that promotes resistance to M. tuberculosis infection by potentiating T(H) cells response to IL-12.
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: Aurelie A
authors.initials: AA
authors.lastname: Ray
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Fountain
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors.forename: Halli E
authors.initials: HE
authors.lastname: Miller
authors.affiliation: Trudeau Institute, Saranac Lake, New York, USA.
authors.forename: Andrea M
authors.initials: AM
authors.lastname: Cooper
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA rrobinson@mcw.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Robinson
mesh_terms: D016475:3T3 Cells; D017398:Alternative Splicing; D000818:Animals; D058491:Bacterial Load / Q000276:immunology; D002460:Cell Line; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology; D053707:Receptors, Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C508440:Il12rb1 protein, mouse; D020033:Protein Isoforms; D053707:Receptors, Interleukin-12; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma