Th9 cells provide Protective TB Immunity

Mei Xia¹Azra Blazevic¹Huan Ning¹Christopher Eickhoff¹Chad E Storer²Richard D Head²Jianguo Liu¹Jessica Jarvela³David Stoeckel¹Erin Rakey¹Jan Tennant¹Daniel L Miller¹Katie Holloway¹Richard F Silver³Daniel Fredric Hoft^1*

• ¹Saint Louis University, St. Louis, United States
• ²Washington University in St. Louis, St. Louis, Missouri, United States
• ³Case Western Reserve University, Cleveland, Ohio, United States

CD4+ Th9 cells have been associated with inflammatory and allergic diseases. IL-9/Th9 can function as both positive and negative immune regulators, but their protective effects against Mycobacterium tuberculosis(Mtb) are unknown. We found that Th9 cells were associated with mycobacteria-specific T cell responses primed by latent tuberculosis infection and BCG vaccination. To study TB-specific Th9 protective effects, we generated Th9 cells from ESAT6-specific TCR transgenic mice and healthy human donors. Both murine and human Th9 cells significantly inhibited intracellular mycobacterial growth. In both in vitro models, IL-9 neutralization strongly reduced Th9 protective effects, and IL-9 treatment alone inhibited intracellular mycobacteria. ESAT-6-specific Th9 and Th1 cells were adoptively transferred into naïve Rag1/2-/- recipients before aerosol Mtb infection. Th9 cells provided robust immunity as protective as Th1 cells, significantly reducing bacteria and pathologic changes post-infection. Differential persistence of Th9 vs. Th1 cell phenotypes was confirmed in vivo, and lung tissue qRT-PCR studies demonstrated the absence of IFN-γ responses in Th9-transferred mice, combined with unique expression of the Th9 specific markers IL-9, IL-10 and PU.1. Therefore, Th9 cells can provide important protection against Mtb infection, and should be targeted with future TB vaccine strategies. Furthermore, Th9 cells appear to utilize a novel protective mechanism independent from Th1-mediated protective responses.