Up-regulation of alternate co-stimulatory molecules on proinflammatory CD28null T cells in bronchiolitis obliterans syndrome

Abstract

Bronchiolitis obliterans syndrome (BOS) is associated with lack of immunosuppression of T cell proinflammatory cytokines and increased T cell granzyme B. Repeated antigen-driven proliferation down-regulates T cell CD28. We hypothesized that down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules (CD134, CD137, CD152 and CD154) on T cells may be associated with BOS. Co-stimulatory molecules, granzyme B, perforin and intracellular cytokines were measured by flow cytometry on T cells from stable lung transplant patients (n = 38), patients with BOS (n = 20) and healthy controls (n = 10). There was a significant increase in the percentage of CD4/28null and CD8/28null T cells producing granzyme B, interferon (IFN)-γ and tumour necrosis factor (TNF)-α in BOS compared with stable patients. Down-regulation of CD28 was associated with steroid resistance and up-regulation of CD134, CD137, CD152 and CD154 on CD4+ T cells and CD137 and CD152 on CD8+ T cells. There was a significant correlation between increased CD28null/CD137 T cells producing IFN-γ, TNF-α with BOS grade (r = 0•861, P < 0•001 for CD28null/CD137 IFN-γ/CD8) and time post-transplant (r = 0•698, P < 0•001 for CD28null/CD137 IFN-γ/CD8). BOS is associated with down-regulation of CD28 and up-regulation of alternate co-stimulatory molecules on steroid-resistant peripheral blood proinflammatory CD4+ and CD8+ T cells. Therapeutic targeting of alternate co-stimulatory molecules on peripheral blood CD28null T cells and monitoring response using these assays may help in the management of patients with BOS.