Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3

Under normal circumstances, the respiratory tract maintains immune tolerance in the face of constant antigen provocation.Using a murine model of tolerance induced by repeated exposure to a low dose of aerosolized antigen, we show an important contribution by CD4 + T cells in the establishment and maintenance of tolerance.The CD4 + T cells expressed both cell surface and soluble TGF- and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice.While cells expressing cell surface TGF- were detectable in mice with inflammation, albeit at a lower frequency compared with that in tolerized mice, only those from tolerized mice expressed FOXP3.Blockade of TGF- in vitro and in vivo interfered with immunosuppression.Although cells that expressed TGF- on the cell surface (TGF- + ), as well as the ones that did not (TGF- -), secreted equivalent levels of soluble TGF-, only the former were able to blunt the development of an allergic phenotype in mice.Strikingly, separation of the TGF- + cells from the rest of the cells allowed the TGF- -cells to proliferate in response to antigen.We propose a model of antigen-induced tolerance that involves cell-cell contact with regulatory CD4 + T cells that coexpress membrane-bound TGF- and FOXP3.Nonstandard abbreviations used: aerosolized antigen (Ag); bronchoalveolar lavage (BAL); cAMP-responsive element binding-1 (CREB-1); lymphotoxin (LT); nuclear factor of activated T cells-c1 (NFATc1); peridinin chlorophyll-a protein (PerCP); phycoerythrin (PE); signal transducer and activator of transcription-6 (STAT-6); T regulatory cell (Treg).