Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-β and FOXP3
Marina Ostroukhova, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, Anuradha Ray
Marina Ostroukhova, Carole Seguin-Devaux, Timothy B. Oriss, Barbara Dixon-McCarthy, Liyan Yang, Bill T. Ameredes, Timothy E. Corcoran, Anuradha Ray
View: Text | PDF
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

×

Figure 11

Options: View larger image (or click on image) Download as PowerPoint
Adoptive transfer of TGF-β–expressing cells from tolerized mice into nai...
Adoptive transfer of TGF-β–expressing cells from tolerized mice into naive mice significantly attenuates the development of airway inflammation in the recipient mice. Cells (105) from each group were adoptively transferred into naive BALB/c mice, which were immunized intraperitoneally at the same time with OVA/alum (day 0). The recipients were boosted with OVA/alum 7 days after transfer (day 7) and were challenged by exposure to aerosol of 1% OVA for 7 days, from day 14 to 21. Control mice were immunized with OVA/alum and challenged with aerosolized OVA (not shown). Twenty-four hours after the last OVA challenge, mice were processed for (A) IgE levels in blood, (B) cytokine (IL-13) levels in BAL fluid, and (C and D) pulmonary inflammation. Lung infiltrates were graded as +5 in all TGF-β− cell transfers or in control OVA/OVA immunized mice (not shown) and were between +1 and +2 in mice that received TGF-β+ cells. There were three mice per group, and the results are representative of two independent experiments. *P < 0.05 versus animals that received TGF-β− cells. (E) In separate experiments, after adoptive transfer of TGF-β+ or TGF-β− cells and immunization with OVA/alum, splenic CD4+ T cells were isolated by positive selection from two recipients in each group on day 14. Cells were stimulated with OVA/APCs for 5 days in vitro. Nuclear extracts were prepared and subjected to Western blot analysis for GATA-3 and STAT-6.