IL12RBeta1 Alternative Splice Variant in the Regulation of IL12 Family Signaling

Robinson, Richard

Abstract

IL12RB1 encodes a transmembrane-spanning protein that serves as the low-affinity receptor for members of the interleukin-12 (ILI 2) family of cytokines. Humans that are homozygous for non-functioning alleles of IL12RB1 exhibit both increased susceptibility to mycobacterial infection and a dysfunction of CD4* T cell - mediated immunity. In the course of examining cellular responses to Mycobacterium tuberculosis, we have observed in activated dendritic cells (DC) and in M. tuberculosis infected lungs the expression of an alternatively spliced 1L12R|31 mRNA that lacks a transmembrane-encoding exon. Termed 1L12RP1ATM, this mRNA is expressed by DCs upon exposure to M. tuberculosis and is observable both in vitro and in vivo. Transient transfection experiments using the N1H/3T3 cell line suggest that while not substituting for IL12R (31, IL12R|31ATM can function to enhance 1L12R31-dependent signaling. In this proposal we will utilize novel tools to further understand the function and significance of 1L12R|31ATM. Specifically, we will 1) determine how IL12R31ATM contributes to DC function following exposure to M. tuberculosis, 2) define which subunits of the 1L12RP1ATM protein are required for its ability to enhance lL12R31-dependent signaling and 3) determine where 1L12R31ATM is induced in the lung following M. tuberculosis infection. Public Health Relevance: 1L12 family members are critical regulators of many classes of immune cells, and our preliminary studies have uncovered a potential novel regulator of I LI 2 signaling, 1L12R31ATM. Using established models of tuberculosis and DC function, the data generated by this application will address basic questions of IL12R31ATM's biological function and consequently allow for a refined model of M. tuberculosis- nduce6, 1L12RP1-dependent immunity to be developed. However, given the importance of 1L12R31 to many diseases, any novel discoveries involving 1L12RP1-signaling and its regulation will have implications beyond TB and will be of interest the greater scientific community.