Mycobacterium tuberculosis infection induces il12rb1 splicing to generate a novel IL-12Rβ1 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) il12rb1 Delta TM that encodes the protein IL-12R beta 1 Delta TM. Compared with IL-12R beta 1, IL-12R beta 1 Delta TM contains an altered C-terminal sequence and lacks a transmembrane domain. Expression of IL-12R beta 1 Delta TM occurs in CD11c(+) cells in the lungs during M. tuberculosis infection. Selective reconstitution of il12rb1(-/-) DCs with (mRNA) il12rb1 and/or (mRNA) il12rb1 Delta TM demonstrates that IL-12R beta 1 Delta TM augments IL-12R beta 1-dependent DC migration and activation of M. tuberculosis-specific T cells. It cannot mediate these activities independently of IL12R beta 1. We hypothesize that M. tuberculosis-exposed DCs express IL-12R beta 1 Delta TM to enhance IL-12R beta 1-dependent migration and promote M. tuberculosis-specific T cell activation. IL-12R beta 1 Delta TM thus represents a novel positive-regulator of IL12R beta 1-dependent DC function and of the immune response to M. tuberculosis.