REDUCED IL-10 SECRETION BY CD4(-LYMPHOCYTES EXPRESSING MUTANT CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR)() T)

Expression of the CFTR protein is thought to be physiologically import ant only in exocrine epithelial cells. However, chronic respiratory in flammation and infection remain unexplained phenomena in disease patho genesis. Non-transformed, antigen-responsive CD4(+) T cells cloned fro m healthy controls and CF patients homozygous or heterozygous for the delta F508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF pa tients displayed equivalent Ca2+-mediated Cl- current; however, TCC fr om patients with CF but not controls displayed defective cAMP-mediated Cl- current. Although CF-derived TCC preserved mitogen and antigen pr oliferative responses and specificity to tetanus toroid epitopes, they selectively secreted approximate to 45% less IL-10 compared with cont rol TCC after activation with concanavalin A (Con A) (624 +/- 101 vers us 1564 +/- 401 pg/ml per 10(6) cells, respectively; P = 0.04) or anti -CD3/phorbol ester (5148 +/- 1634 versus 11 788 +/- 2390 pg/ml; P = 0. 05). This difference was independent of atopy. Secretion of interferon -gamma, IL-2, and IL-4 was comparable in CF and control TCC after both forms of activation, while IL-5 was reduced in CF TCC following anti- CD3/phorbol myristate acetate (PMA) but not after Con A. We conclude t hat expression of mutant CFTR in human TCC is accompanied by ion chann el dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL-10 secretion after polyclonal activation. It is p ossible that disruption of IL-10-mediated antiinflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.