Reduced IL-10 secretion by CD4+ T lymphocytes expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR)

Abstract

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 δF508 mutation transcribed CFTR mRNA and expressed immunoreactive cytoplasmic CFTR protein. T cell clones (TCC) from controls and CF patients displayed equivalent Ca2+‐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 ≈ 45% less IL‐10 compared with control TCC after activation with concanavalin A (Con A) (624 ± 101 versus 1564 ± 401 pg/ml per 106 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 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.

The pros and cons of immunomodulatory IL-10 gene therapy with recombinant AAV in a Cftr−/−-dependent allergy mouse model

“…[15][16][17][18] These results along with other studies suggest that IL-10 deficiency in CF plays a major role in the dysregulation of inflammatory responses observed in cystic fibrosis. [19][20][21] For these reasons much interest has been focused on the potential role that IL-10 plays in the altered inflammatory and infectious lung processes in CF.…”

Aspergillus fumigatus Generates an Enhanced Th2-Biased Immune Response in Mice with Defective Cystic Fibrosis Transmembrane Conductance Regulator

“…The lung disease in CF is characterized by persistent inflammation, infection, and mucus hypersecretion (51) and studies thus far have not yielded a clear picture of disease pathogenesis. Lymphocytes express CFTR and therefore may be affected by defects in this channel (26,(52)(53)(54)(55)(56). Lymphocytes are also present in sizable aggregates within the subepithelial space of the CF airway (6), positioning them to function as important regulators of airway inflammation.…”

Functional IL-10 Deficiency in the Lung of Cystic Fibrosis (cftr−/−) and IL-10 Knockout Mice Causes Increased Expression and Function of B7 Costimulatory Molecules on Alveolar Macrophages

“…This is consistent with the idea that airway epithelial cells, which are the likely source of the IL-10 in the normal lung (1, 2), may be more dependent on CFTR for their normal function, including IL-10 production, than many other types of cells. Lymphocytic cell lines and lymphoblasts have been shown to express CFTR, and T cell lines from CF patients have been shown to produce less IL-10 than comparable cells from healthy individuals (43,44). However, those differences are not as great as the differences in IL-10 content of BAL documented in CF vs normal patients and CFTR Ϫ/Ϫ vs CFTR ϩ/ϩ mice.…”