Xie, Markus M.Liu, HongCorn, CalebKoh, Byung-HeeKaplan, Mark H.Turner, Matthew J.Dent, Alexander L.2020-06-252020-06-252019-07-12Xie, M. M., Liu, H., Corn, C., Koh, B. H., Kaplan, M. H., Turner, M. J., & Dent, A. L. (2019). Roles of T Follicular Helper Cells and T Follicular Regulatory Cells in Autoantibody Production in IL-2-Deficient Mice. ImmunoHorizons, 3(7), 306–316. https://doi.org/10.4049/immunohorizons.1900034https://hdl.handle.net/1805/23102Autoantibodies can result from excessive T follicular helper (Tfh) cell activity, whereas T follicular regulatory (Tfr) cells negatively regulate autoantibody production. IL-2 knockout (KO) mice on the BALB/c background have elevated Tfh responses, produce autoantibodies, and develop lethal autoimmunity. We analyzed Tfh and Tfr cells in IL-2 KO mice on the C57BL/6 (B6) genetic background. In B6 IL-2 KO mice, the spontaneous formation of Tfh cells and germinal center B cells was greatly enhanced, along with production of anti-DNA autoantibodies. IL-2 has been reported to repress Tfr cell differentiation; however, Tfr cells were not increased over wild-type levels in the B6 IL-2 KO mice. To assess Tfh and Tfr cell regulation of autoantibody production in IL-2 KO mice, we generated IL-2 KO mice with a T cell-specific deletion of the master Tfh cell transcription factor Bcl6. In IL-2 KO Bcl6 conditional KO (2KO-Bcl6TC) mice, Tfh cells, Tfr cells, and germinal center B cells were ablated. In contrast to expectations, autoantibody IgG titers in 2KO-Bcl6TC mice were significantly elevated over autoantibody IgG titers in IL-2 KO mice. Specific deletion of Tfr cells with Foxp3-cre Bcl6-flox alleles in IL-2 KO mice led to early lethality, before high levels of autoantibodies could develop. We found IL-2+/+ Tfr cell-deficient mice produce significant levels of autoantibodies. Our overall findings provide evidence that Tfh cells are dispensable for high-level production of autoantibodies and also reveal a complex interplay between Tfh and Tfr cells in autoantibody production and autoimmune disease.en-USPublisher PolicyAutoimmunityAutoantibodiesT follicular helper cellsT follicular regulatory T cellsIL-2Regulatory T cellsArticle