Activation of naturally occurring lung CD4⁺CD25⁺ regulatory T cells requires CD8 and MHC I interaction

Naturally occurring Foxp3⁺CD4⁺CD25⁺ T cells (nTregs) isolated from lungs of naive mice regulate allergic airway hyperresponsiveness (AHR) and inflammation. Here, we demonstrate the critical requirement for engagement of MHC class I on CD4⁺CD25⁺ T cells by CD8 for the functional activation of these nTregs. Suppression of allergen-induced AHR and inflammation by nTregs was abolished in mice treated with anti-CD8. Correspondingly, decreased levels of IL-10 and TGF-β and increased levels of Th2 cytokines in bronchoalveolar lavage were detected in these treated mice. Similarly, nTregs isolated from β2m^-/- mice or from mice treated with anti-MHC I antibody in vitro before intratracheal transfer failed to modulate AHR or inflammation. Coculture of nTregs with CD8⁺ T cells increased IL-10 and TGF-β. Addition of anti-MHC I or anti-CD8 reduced IL-10 and TGF-β. These results demonstrate that functional activation of nTregs requires the interaction between MHC I on CD4⁺CD25⁺ T cells and CD8.