AUTHOR=Hall Bruce M., Tran giang T., Verma Nirupama , Plain Karren , Robinson Catherine M., Nomura Masaru , Hodgkinson Suzanne J. TITLE=Do Natural T Regulatory Cells become Activated to Antigen Specific T Regulatory Cells in Transplantation and in Autoimmunity? JOURNAL=Frontiers in Immunology VOLUME=4 YEAR=2013 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2013.00208 DOI=10.3389/fimmu.2013.00208 ISSN=1664-3224 ABSTRACT=

Antigen specific T regulatory cells (T_reg) are often CD4⁺CD25⁺FoxP3⁺ T cells, with a phenotype similar to natural T_reg (nT_reg). It is assumed that nT_reg cannot develop into an antigen specific T_reg as repeated culture with IL-2 and a specific antigen does not increase the capacity or potency of nT_reg to promote immune tolerance or suppress in vitro. This has led to an assumption that antigen specific T_reg mainly develop from CD4⁺CD25⁻FoxP3⁻ T cells, by activation with antigen and TGF-β in the absence of inflammatory cytokines such as IL-6 and IL-1β. Our studies on antigen specific CD4⁺CD25⁺ T cells from animals with tolerance to an allograft, identified that the antigen specific and T_reg are dividing, and need continuous stimulation with specific antigen T cell derived cytokines. We identified that a variety of cytokines, especially IL-5 and IFN-γ but not IL-2 or IL-4 promoted survival of antigen specific CD4⁺CD25⁺FoxP3⁺ T_reg. To examine if nT_reg could be activated to antigen specific T_reg, we activated nT_reg in culture with either IL-2 or IL-4. Within 3 days, antigen specific T_reg are activated and there is induction of new cytokine receptors on these cells. Specifically nT_reg activated by IL-2 and antigen express the interferon-γ receptor (IFNGR) and IL-12p70 (IL-12Rβ2) receptor but not the IL-5 receptor (IL-5Rα). These cells were responsive to IFN-γ or IL-12p70. nT_reg activated by IL-4 and alloantigen express IL-5Rα not IFNGR or IL-12p70Rβ2 and become responsive to IL-5. These early activated antigen specific T_reg, were respectively named Ts1 and Ts2 cells, as they depend on Th1 or Th2 responses. Further culture of Ts1 cells with IL-12p70 induced Th1-like T_reg, expressing IFN-γ, and T-bet as well as FoxP3. Our studies suggest that activation of nT_reg with Th1 or Th2 responses induced separate lineages of antigen specific T_reg, that are dependent on late Th1 and Th2 cytokines, not the early cytokines IL-2 and IL-4.