Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rbeta1 isoform that enhances DC migration.
RNA splicing is an increasingly recognized regulator of immunity. Here, we demonstrate that after Mycobacterium tuberculosis infection (mRNA) il12rb1 is spliced by dendritic cells (DCs) to form an alternative (mRNA) il12rb1Deltatm that encodes the protein IL-12Rbeta1DeltaTM. Compared with IL-12Rbeta1, IL-12Rbeta1DeltaTM contains an altered C-terminal sequence and lacks a transmembrane domain. Expression of IL-12Rbeta1DeltaTM occurs in CD11c(+) cells in the lungs during M. tuberculosis infection. Selective reconstitution of il12rb1(-/-) DCs with (mRNA) il12rb1 and/or (mRNA) il12rb1Deltatm demonstrates that IL-12Rbeta1DeltaTM augments IL-12Rbeta1-dependent DC migration and activation of M. tuberculosis-specific T cells. It cannot mediate these activities independently of IL12Rbeta1. We hypothesize that M. tuberculosis-exposed DCs express IL-12Rbeta1DeltaTM to enhance IL-12Rbeta1-dependent migration and promote M. tuberculosis-specific T cell activation. IL-12Rbeta1DeltaTM thus represents a novel positive-regulator of IL12Rbeta1-dependent DC function and of the immune response to M. tuberculosis.
Robinson
Richard T
RT
Trudeau Institute, Inc., Saranac Lake, NY 12983, USA.
Khader
Shabaana A
SA
Martino
Cynthia A
CA
Fountain
Jeffrey J
JJ
Teixeira-Coelho
Maria
M
Pearl
John E
JE
Smiley
Stephen T
ST
Winslow
Gary M
GM
Woodland
David L
DL
Walter
Michael J
MJ
Conejo-Garcia
Jose R
JR
Gubler
Ueli
U
Cooper
Andrea M
AM
D017398:Alternative Splicing; D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology; D002465:Cell Movement; D054415:Chemokine CCL19 / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology* / Q000502:physiology; D007700:Kinetics; D008168:Lung / Q000276:immunology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics; D053707:Receptors, Interleukin-12 / Q000172:deficiency / Q000235:genetics* / Q000276:immunology
D054415:Chemokine CCL19; C508440:Il12rb1 protein, mouse; D012333:RNA, Messenger; D053707:Receptors, Interleukin-12