Chronic human lung allograft rejection is manifested by bronchiolitis obliterans syndrome (BOS). BOS has a multifactorial etiology. Previous studies have indicated that both cellular and humoral alloimmunity play a significant role in the pathogenesis of BOS. Recently, autoimmunity has also been demonstrated to contribute to lung allograft rejection in animal models. However, the significance of autoimmunity in BOS remains unknown. In this report, we investigated the role of naturally occurring CD4+CD25+ regulatory T cells (T-regs) in modulating cellular autoimmunity to collagen type V (col-V), a ‘sequestered’ yet immunogenic self-protein present in the lung tissue, following lung transplantation (LT). We demonstrated that col-V reactive CD4+ T cells could be detected in the peripheral blood of lung transplant recipients. There was a predominance of IL-10 producing T cells (TIL-10) reactive to col-V with significantly lower levels of IFN-γ and IL-2 producing T cells (Th1 cells). The col-V specific TIL-10 cells suppressed the proliferation and expansion of col-V specific Th1 cells by IL-10-dependent and contact-independent pathways. The TIL-10 cells were distinct but their development was dependent on the presence of T-regs. Furthermore, during chronic lung allograft rejection there was a significant decline of TIL-10 cells with concomitant expansion of col-V-specific IFN-γproducing Th1 cells.