Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR).
Expression of the CFTR protein is thought to be physiologically important only in exocrine epithelial cells. However, chronic respiratory inflammation and infection remain unexplained phenomena in disease pathogenesis. Non-transformed, antigen-responsive CD4+ T cells cloned from 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 patients displayed equivalent Ca(2+)-mediated Cl- current; however, TCC from patients with CF but not controls displayed defective cAMP-mediated Cl-current. Although CF-derived TCC preserved mitogen and antigen proliferative responses and specificity to tetanus toxoid epitopes, they selectively secreted approximately 45% less IL-10 compared with control TCC after activation with concanavalin A (Con A) (624 +/- 101 versus 1564 +/- 401 pg/ml per 10(6) cells, respectively; P = 0.04) or anti-CD3/phorbol ester (5148 +/- 1634 versus 11788 +/- 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 that expression of mutant CFTR in human TCC is accompanied by ion channel dysfunction characteristic of the CF phenotype, and is accompanied by a reduction in IL-10 secretion after polyclonal activation. It is possible that disruption of IL-10-mediated anti-inflammatory homeostasis may contribute to early onset sustained inflammation in CF airways.
Moss
R B
RB
Department of Pediatrics, Stanford University School of Medicine, CA 94305-5119, USA.
Bocian
R C
RC
Hsu
Y P
YP
Dong
Y J
YJ
Kemna
M
M
Wei
T
T
Gardner
P
P
D000818:Animals; D015139:Blotting, Southern; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D002461:Cell Line, Transformed; D002999:Clone Cells; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers; D015342:DNA Probes; D006801:Humans; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000378:metabolism*; D008213:Lymphocyte Activation; D051379:Mice; D018613:Microscopy, Confocal; D008934:Mitogens; D009154:Mutation; D016133:Polymerase Chain Reaction; D011817:Rabbits
C505032:CFTR protein, human; D017931:DNA Primers; D015342:DNA Probes; D008934:Mitogens; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D016753:Interleukin-10