Tolerance induced by inhaled antigen involves CD4(+) T cells expressing membrane-bound TGF-beta 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-beta and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice. While cells expressing cell surface TGF-beta 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-beta in vitro and in vivo interfered with immunosuppression. Although cells that expressed TGF-beta on the cell surface (TGF-beta(+)), as well as the ones that did not (TGF-beta(-)), secreted equivalent levels of soluble TGF-beta, only the former were able to blunt the development of an allergic phenotype in mice. Strikingly, separation of the TGF-beta(+) cells from the rest of the cells allowed the TGF-beta(-) 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-beta and FOXP3.
Ostroukhova
Marina
M
Department of Medicine, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Seguin-Devaux
Carole
C
Oriss
Timothy B
TB
Dixon-McCarthy
Barbara
B
Yang
Liyan
L
Ameredes
Bill T
BT
Corcoran
Timothy E
TE
Ray
Anuradha
A
D000280:Administration, Inhalation; D019264:Adoptive Transfer; D000336:Aerosols; D000818:Animals; D000941:Antigens / Q000008:administration & dosage / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D051858:Forkhead Transcription Factors; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000235:genetics*
D000336:Aerosols; D000941:Antigens; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016212:Transforming Growth Factor beta; D010047:Ovalbumin