CD9+ Regulatory B Lymphocytes Control Chronic Lung Inflammation by Inducing Effector T Cell Apoptosis

Abstract

The occurrence of chronic lung allograft dysfunction (CLAD) is the main complication after lung transplantation (LT) and remains the most common cause of graft failure and death. Currently, the available immunosuppressive therapies cannot prevent its occurrence in 50% of patients at 5 years. Conversely, some LT recipients, remain free of CLAD for a long time, and are considered as stable (STA). Whereas in kidney transplantation, predictive B-cell signature of long term or poor graft outcome have been identified by us and others, nothing has been done yet in lung transplantation. We aim to identify and validate predictive B lymphocyte signatures in order to identify and lighten the risk of CLAD and allow for early intervention before irreversible damages. PBMCs from the Lung Transplanted patients (COLT) COhort were immunophenotyped before LT, and at regular time points after LT. PBMCs from 21 patients with bronchiolitis obliterans syndrome and 21 patients with long-term functional stability (STA) were analyzed. 20 healthy volunteers (HV) were analyzed as controls. Cells were stained for the B-cell markers CD19, CD27, CD38, CD138, CD22, CD24, IgD, IgM, CD5 and CD9 to determine the percentage of transitional, naive, plasmablast, memory and regulatory B-cells. No differences were observed between the groups for CD19+ B cells, naive, memory and plasma B cells. However, both the level of CD38hiCD24hi transitional and CD9+ B cells secreting IL-10 were highly associated with bronchiolitis obliterans syndrome–free survival at 24 months after lung transplantation before the appearance of symptoms. Patients with CD9+ or transitional B cell frequency below 5.4% and 2.24%, respectively (sensitivity = 100%), displayed significantly higher incidence of bronchiolitis obliterans syndrome. In summary, these data associate IL-10-secreting CD24hiCD38hi transitional and CD9+ B cells with better allograft outcome in LT patients. B cell subsets and possibly their production of IL-10 may contribute to create a favorable environment that might be essential for the maintenance of long-term stable graft function. The identification of CD9-expressing B cells as a new predictive biomarker of bronchiolitis obliterans syndrome–free survival provide new strategies for prediction and treatment of the pathology.