Expansion of CD4loCD14+CD40+ LKLF Hi CD4+ T cells correlates with acute pulmonary inflammation and provides a mechanism for impaired pathogen clearance in Cystic Fibrosis (39.24)

Abstract Cystic Fibrosis (CF) is characterized by chronic infection of the lung by bacterial pathogens with a subsequent robust but ineffectual neutrophilic immune response. As a result, patients' airways sustain irreversible injury, with respiratory failure accounting for >80% of deaths from the disease. Examination of lymphocyte/monocyte subsets in the peripheral blood of CF patients revealed a greatly expanded CD4+ T cell subset characterized by a very high expression level of the cell survival/quiescence transcription factor Lung Kruppel Like Factor, LKLF. Furthermore, cells exhibited co-expression of CD40 as well as the pattern recognition coreceptor CD14. Importantly, this observation was mirrored in airway submucosa and pulmonary lymph nodes isolated from CF lung transplant recipients. In a majority of patients, this expanded T cell subset from the peripheral blood was found to produce high levels of IL-4, which coincides with previous observations of Th-2 bias in CF patients infected with Pseudomonas aeruginosa. In vitro assays illustrated that simultaneous cross-linking of CD40 and CD3 on this T cell subset results in the elevation of LKLF. Paired with previous observations of elevated circulating soluble CD40 ligand in CF patients that correlate with worse pulmonary function, this data suggests a mechanism for the persistence of the deleterious Th-2 cytokine producing T cells that hamper the effectual clearance of lung pathogen. Importantly alterations in cell number within this T cell subtype from the peripheral blood correlate with observed severity of pulmonary inflammation and provide a means of evaluating efficacy of treatment. Research support;NIH:DDK (Wagner),Cystic Fibrosis Foundation(Saavedra)