CD28 and CTLA4 coordinately regulate airway inflammatory cell recruitment and T-Helper cell differentiation after inhaled allergen

Airway inflammation after inhaled allergen exposure requires the recruitmen t, activation, and differentiation of antigen-specific T cells into T helpe r (Th) 2 effector cells. These processes are regulated not only by antigen engagement of the T-cell receptor, but also by specific accessory molecules on the surface of the T cell. We examined how the balance of signals deriv ed through the CD28 and cytotoxic T-lymphocyte antigen (CTLA) 4 receptors m odulate the outcome of inhaled antigen exposure in a murine model of allerg ic airway inflammation. Mice deficient in CD28 have defective Th2 cell deve lopment and failed to develop inflammation after sensitization and inhaled challenge with ovalbumin. Prevention of B7-CTLA4 interactions in CD28-defic ient mice restored lymphocyte but not eosinophil recruitment to the airway. Analysis of cytokine gene expression revealed that T cells from CD28-defic ient mice failed to differentiate into Th2 cells in either the presence or absence of B7-dependent signals, and therefore did not recruit eosinophils to the airway. Thus, the processes of T-cell recruitment to the airway and T-cell differentiation have distinct requirements for signals mediated thro ugh the CD28 and CTLA4 receptors, demonstrating that these receptors are im portant regulatory components in the development of allergic airway inflamm ation.