Divergence in NK cell and cyclic AMP regulation of T cell CD40L expression in asthmatic subjects.
T cells are central in the pathogenesis of asthma, and the associated ligand, CD40L, plays an important role by increasing production of immunoglobulin E and inflammatory mediators. beta-Adrenoceptor agonists are commonly used in asthma, although little is known regarding effects on CD40L expression and T cell activation. Here, we demonstrate that cyclic adenosine monophosphate (cAMP) and beta-adrenoceptor agonists differentially regulate CD40L in asthma. cAMP increased naïve T cell CD40L expression in asthmatics (9.8+/-8.5 increase in percent CD40L-positive cells), and expression in control subjects was inhibited (7.1+/-6.0 decrease in percent CD40L-positive cells; P< 0.05). Cell depletion and reconstitution experiments were used to determine that cAMP enhancement of CD40L required cell-to-cell contact with an asthma-associated natural killer (NK) cell subset. The NK cell subset expressed elevated levels of CD95, and in vitro-generated CD95+ NK2 cells also produced similar effects on CD40L expression. Our findings suggest that a subset of NK cells with elevated CD95 expression is associated with asthma and can reverse cAMP inhibitory effects on T cell CD40L with the potential to increase disease exacerbation.
Wingett
Denise
D
Research Service, Department of Veterans Affairs Medical Center, Boise, Idaho 83702, USA. denise.wingett@med.va.gov
Nielson
Christopher P
CP
D001249:Asthma / Q000276:immunology*; D023201:CD40 Ligand / Q000032:analysis*; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000502:physiology*; D006801:Humans; D007694:Killer Cells, Natural / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000032:analysis; D013601:T-Lymphocytes / Q000737:chemistry*; D019014:fas Receptor / Q000032:analysis
D019014:fas Receptor; D023201:CD40 Ligand; D000242:Cyclic AMP; D017493:Leukocyte Common Antigens