REVIEW ARTICLE

Front. Immunol., 02 August 2013 | doi: 10.3389/fimmu.2013.00208

Do natural T regulatory cells become activated to antigen specific T regulatory cells in transplantation and in autoimmunity?

Bruce M. Hall*, Giang T. Tran, Nirupama D. Verma, Karren M. Plain, Catherine M. Robinson, Masaru Nomura and Suzanne J. Hodgkinson

Immune Tolerance Laboratory, Medicine, University of New South Wales, Sydney, NSW, Australia

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.

Keywords: antigen specific T_reg, nT_reg, Th1-like T_reg, Th2-like T_reg, immune tolerance

Citation: Hall BM, Tran GT, Verma ND, Plain KM, Robinson CM, Nomura M and Hodgkinson SJ (2013) Do natural T regulatory cells become activated to antigen specific T regulatory cells in transplantation and in autoimmunity? Front. Immunol. 4:208. doi: 10.3389/fimmu.2013.00208

Received: 03 April 2013; Accepted: 08 July 2013;
Published online: 02 August 2013.

Edited by:

Eyad Elkord, United Arab Emirates University, UAE; University of Salford, UK; University of Manchester, UK

Reviewed by:

Dominique M. A. Bullens, KU Leuven, Belgium
Jocelyne Demengeot, Instituto Gulbenkian de Ciencia, Portugal

Copyright: © 2013 Hall, Tran, Verma, Plain, Robinson, Nomura and Hodgkinson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bruce M. Hall, Immune Tolerance Laboratory, Medicine, University of New South Wales, Suite 206 National Innovation Centre, 4 Cornwallis Street, Australian Technology Park, Eveleigh, Sydney, NSW 1430, Australia e-mail: b.hall@unsw.edu.au