Abstract
T cell-mediated autoimmunity to collagen V (col-V), a sequestered yet immunogenic self-protein, can induce chronic lung allograft rejection in rodent models. In this study we characterized the role of CD4 super(+)CD25 super(+) regulatory T cells (Tregs) in regulating col-V autoimmunity in human lung transplant (LT) recipients. LT recipients revealed a high frequency of col-V-reactive, IL-10-producing CD4 super(+) T cells (T sub(IL-10) cells) with low IL-2-, IFN- gamma -, IL-5-, and no IL-4-producing T cells. These T sub(IL-10) cells were distinct from Tregs because they lacked constitutive expression of both CD25 and Foxp3. Expansion of T sub(IL-10) cells during col-V stimulation in vitro involved CTLA-4 on Tregs, because both depleting and blocking Tregs with anti-CTLA4 F(ab') sub(2) mAbs resulted in loss of T sub(IL-10) cells with a concomitant increase in IFN- gamma producing Th1 cells (TIFN- gamma cells). A Transwell culture of col-V-specific T sub(IL-10) cells with Th1 cells (those generated in absence of Tregs) from the same patient resulted in marked inhibition of IFN- gamma and proliferation of T sub(IFN- gamma ) cells, which was reversed by neutralizing IL-10. Furthermore, the T sub(IL-10) cells were HLA class II restricted because blocking HLA class II on APCs resulted in the loss of IL-10 production. Chronic lung allograft rejection was associated with the loss of Tregs with a concomitant decrease in T sub(IL-10) cells and an increase in T sub(IFN- gamma ) cells. We conclude that LT patients have col-V-specific T cells that can be detected in the peripheral blood. The predominant col-V-specific T cells produce IL-10 that suppresses autoreactive Th1 cells independently of direct cellular contact. Tregs are pivotal for the induction of these "suppressor" T sub(IL-10) cells.