Reversibility with interleukin-2 suggests that T cell anergy contributes to donor-specific hyporesponsiveness in renal transplant patients

Data from various rodent models have implicated a role for anergic T cells in the maintenance of self and transplantation tolerance. The relevance of donor-specific T cell anergy to clinical transplantation, however, has not been demonstrated. Previous studies have reported that recipients of solid organ transplant often have reduced frequencies of CD4⁺ T cells with anti-donor direct pathway allospecificity after transplantation. The underlying mechanism(s) of this donor-specific hyporesponsiveness is unclear but likely to contribute to the diminished immunosuppressive requirement of transplant patients with time after transplantation. This study shows that ex vivo treatment of CD4⁺ T cells from renal transplant recipients with IL-2 could specifically increase the anti-donor frequency in all the patients with evidence of donor-specific hyporesponsiveness. It also shows that the IL-2-induced recovery of anti-donor frequency is unlikely to result from non-specific stimulation or selective clonal expansion of activated, allospecific CD4⁺ T cells. Taken together, the data suggest that T cell anergy plays an important role in the direct pathway hyporesponsiveness that evolves in many human renal transplant recipients.