Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3
Marina Ostroukhova, … , Timothy E. Corcoran, Anuradha Ray
Marina Ostroukhova, … , Timothy E. Corcoran, Anuradha Ray
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):28-38. https://doi.org/10.1172/JCI20509.
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Article Immunology

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

Abstract

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-β and inhibited the development of an allergic phenotype when adoptively transferred to naive recipient mice. While cells expressing cell surface TGF-β 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-β in vitro and in vivo interfered with immunosuppression. Although cells that expressed TGF-β on the cell surface (TGF-β+), as well as the ones that did not (TGF-β–), secreted equivalent levels of soluble TGF-β, only the former were able to blunt the development of an allergic phenotype in mice. Strikingly, separation of the TGF-β+ cells from the rest of the cells allowed the TGF-β– 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-β and FOXP3.

Authors

Marina Ostroukhova, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, Anuradha Ray

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CD4+ T cells in tolerized mice express both soluble and membrane-bound T...
CD4+ T cells in tolerized mice express both soluble and membrane-bound TGF-β. On day 34, splenic CD4+ T cells from the two groups of mice (tolerance and airway inflammation), as well as cells from naive animals, were isolated and stimulated with OVA/APCs in vitro for 48 hours. The T cells were then examined for both (A) intracellular and (B) cell-surface expression of TGF-β by flow cytometry. Appropriate isotype controls are shown, and the percentages presented for the stained cells have had the indicated background isotype control levels subtracted. (A) T cells were stained for cell-surface CD4 expression, then were fixed, permeabilized, and stained for intracellular expression of TGF-β. The isotype for CD4 is shown for the naive animals. For the airway inflammation and tolerance conditions, the control is stained for CD4 and for the isotype for TGF-β. (B) T cells were double-stained for cell-surface expression of CD25 and TGF-β.