Nasal tolerance induces antigen-specific CD4⁺CD25^- regulatory T cells that can transfer their regulatory capacity to naive CD4⁺ T cells

The mucosal immune system is uniquely adapted to elicit immune responses against pathogens but also to induce tolerogenic responses to harmless antigens. In mice, nasal application of ovalbumin (OVA) leads to suppression of both T_h1 and T_h2 responses. This tolerance can be transferred to naive mice by CD4⁺ T_r cells from the spleen. Using the allotypic Ly5 system, we were able to demonstrate in vivo that T_r cells not only suppress naive CD4⁺ T cells, but also induce them to differentiate into T_r cells. The effector function of these mucosal T_r cells is not restricted by cytokine polarization, since T_r cells from T_h1-tolerant mice can suppress a T_h2 response and vice versa. Transfer of splenic CD4⁺CD25⁺ and CD4⁺CD25^- T cell subsets from OVA-tolerized mice revealed that both subsets were equally able to suppress a delayed-type hypersensitivity response in acceptor mice. In contrast to the CD25^- T cell subset, the CD25⁺ cells were not specific for the antigen used for tolerization. Together, these findings demonstrate a role for CD4⁺CD25^- T_r cells in mucosal tolerance, which suppresses CD4⁺ T cells in an antigen-specific fashion, irrespective of initial T_h1/T_h2 skewing of the immune response. This offers a major advantage in the manipulation of mucosal tolerance for the treatment of highly cytokine-polarized disorders such as asthma and autoimmune diseases.