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

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.