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Keywords:

  • Allergic lung inflammation;
  • Costimulation;
  • CTLA4-Ig;
  • T-cell activation

Abstract

The T-cell response to antigen depends on coordinate signaling between costimulatory and inhibitory receptors. The altered function of either may underlie the pathophysiology of autoimmune and/or chronic inflammatory diseases and manipulation of these pathways is an important emerging area of therapeutics. We report here that the immunosuppressant drug CTLA4-Ig inhibits the effector phase of allergic airway inflammation through a CD28-independent, nitric oxide synthase (NOS)-dependent mechanism. Using mice deficient in both B- and T-lymphocyte attenuator (BTLA) and CD28, we demonstrate that simultaneous deficiency of an inhibitory receptor can rescue the in vivo but not the in vitro CD28-deficient phenotype. Furthermore, we demonstrate that inflammation in CD28/BTLA-double-deficient mice is suppressed by CTLA4-Ig. This suppression is reversed by treatment with the NOS inhibitor, N6-methyl-L-arginine acetate (L-NMMA). In addition, CTLA4-Ig is ineffective at inhibiting inflammation in NOS2-deficient mice when given at the effector phase. Thus, CD28 and BTLA coordinately regulate the in vivo response to inhaled allergen, and CTLA4-Ig binding to B7-proteins inhibits the effector phase of inflammation by a CD28-independent, NOS-dependent mechanism.