Cystic fibrosis (CF), an autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (
CFTR) gene [
1], is an inherited, life-limiting condition (reviewed in [
2]). The main cause of death is CF lung disease [
3], with a vicious cycle of infection and inflammation and interspersed acute exacerbations [
2]. From early in life the typical CF patient, compared to healthy controls, has evidence of sustained and severe lung inflammation [
4] and CF cells display a hyper-inflammatory phenotype that is ineffective at clearing bacterial pathogens but rather causes progressive tissue damage [
5]. T lymphocytes predominate in the CF airway wall mucosa and submucosa, where the most severe tissue damage is noted in patients with the most advanced lung disease [
6,
7]. Studies have reported a skewing of CF T cell immune responses toward the Th2 and more recently Th17 lineages [
8], with increased levels of pro-inflammatory cytokines of the Th17 family implicated in the destructive acute exacerbations [
9]. In this context, we were surprised to discover that one of our patients with advanced CF lung disease, whilst on the list for lung transplantation, demonstrated evidence of T cell exhaustion with failure of naïve T cells to undergo differentiation into cytokine producing effector cells in response to stimulation. We speculate that an intrinsic, primary impairment of T cell differentiation may have contributed to the greater severity of her CF lung disease compared to her peers.