Induction of contrasuppressor cells and loss of immune privilege produced by corneal nerve ablation

P_URPOSE. Severing of corneal nerves in preparation of corneal transplantation abolishes immune privilege of subsequent corneal transplants placed into either eye: a phenomenon termed sympathetic loss of immune privilege (SLIP). SLIP is due to the disabling of T regulatory cells (Tregs) by CD11c⁺ contrasuppressor (CS) cells. This study characterized the induction, function, and manipulation of CS cell activity and the effect of these cells on Tregs induced by anterior chamber-associated immune deviation (ACAID). M_ETHODS. CS cells were induced using a 2.0-mm trephine to score the corneal epithelium. CD11c⁺ CS cells were evaluated by adoptive transfer and by their capacity to disable CD8⁺ ACAID Tregs in local adoptive transfer (LAT) of suppression assays. CD11c⁺ cells were deleted from the ocular surface by subconjunctival injection of clodronate-containing liposomes. R_ESULTS. CD11c⁺ CS cell were radiosenstive and long lived. As few as 1000 CS cells blocked the suppressive activity of previously generated CD8⁺ ACAID Tregs, indicating that CS cells act at the efferent arm of the immune response. Depletion of resident CD11c⁺ cells at the ocular surface prevented the generation of CS cells. C_ONCLUSIONS. Corneal nerve injury that occurs during keratoplasty converts ocular surface CD11c⁺ cells into CS cells that block CD8⁺ Tregs, which are induced by introducing antigens into the anterior chamber (i.e., ACAID Tregs). Depletion of CD11c⁺ cells at the ocular surface prevents the generation of CS cells and may be a useful strategy for preventing SLIP and enhancing the survival of second corneal transplants.