T Cell Autophagy a Key Mechanism in Preventing Transplant Rejection

T cell autophagy is crucial for induction of transplant tolerance, according to a study by Divya Anna Verghese, PhD, and colleagues from Mount Sinai School of Medicine. “Our study sets the stage for future work aimed at manipulating autophagy machinery in a clinical setting providing new opportunities to intervene in the alloimmune response,” Verghese said, adding “targeting autophagy could be exploited as a means to manipulate pathogenic and/or protective immunity.”

“The induction and maintenance of stable transplant tolerance involves both regulatory and deletional mechanisms, the latter of which have been attributed to T cell apoptosis,” Verghese noted. “Autophagy is responsible for the degradation of protein aggregates and damaged organelles, and while usually a pro-survival mechanism, it can contribute to cell death.”

Her group observed the costimulatory blockade with anti-CD154 mAb was associated with increased autophagy in allografts and immune cells, and chemical or genetic inhibition of autophagy led to allograft rejection despite donor specific transfusion/MR1. Reconstitution experiments in Rag2-/- mice confirmed that the defect mapped with lymphocytes. “Using mice conditionally deficient for Atg7 we showed that transplant tolerance required intact autophagy in T cells but not in B cells or dendritic cells,” Verghese said. “T cells from autophagy-deficient animals proliferated more, expanded better, and died less in vivo during tolerance induction compared to those from wild type animals, while regulatory T cells from autophagy deficient animals functioned normally.”

Verghese concluded, “our findings indicate autophagy-mediated T cell death is a requisite mechanism underlying transplant tolerance.” Interestingly, she adds “the mTOR inhibitors rapamycin and everolimus are used as part of immunosuppressive regimens and their main effector mechanism is to inhibit T-cell proliferation. Inhibition of mTOR is a potent inducer of autophagy and the use of rapamycin, in combination with costimulatory blockade, provides strong synergy and favors peripheral tolerance.”

December 2012 (Vol. 4, Number 12)