Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

S Yamazaki, T Iyoda, K Tarbell, K Olson… - The Journal of …, 2003 - rupress.org
S Yamazaki, T Iyoda, K Tarbell, K Olson, K Velinzon, K Inaba, RM Steinman
The Journal of experimental medicine, 2003rupress.org
An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T
cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-
presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells
remain to be identified, hampering their study in experimental and clinical situations. CD25+
CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic
antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can …
An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25 autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25 CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25 CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25 CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.
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