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. While autophagy is usually a pro-survival mechanism, it can also contribute to cell death. Herein we tested the hypothesis that autophagy is required for the death of alloreactive T cells and promotes costimulatory blockade-induced tolerance.

We observed that costimulatory blockade with anti-CD154 monoclonal antibody (mAb) was associated with increased autophagy in allografts and immune cells. We examined the importance of autophagy in the induction of transplant tolerance using a mouse model with genetic disruption of the autophagy-related gene beclin1 (becn1). We observed that becn1+/- recipients rejected allografts despite treatment with donor specific transfusion and anti-CD154 mAb. There were no differences in the levels of donor-specific IgG serum antibodies between WT and becn1+/- recipients. We also observed elevated frequencies of IFNΓ producing CD4 T cells within the graft infiltrating lymphocytes in the becn1+/- recipients as compared with WT recipients. Furthermore, using an in vivo cell transfer system, we found that becn1+/- T cells exhibited increased alloreactivity and reduced cell death despite co-stimulatory blockade. This requirement of intact autophagy essential for allograft survival was found to be specific to the T cell compartment but not to B cell or dendritic cell lineages. Together our findings indicate that autophagy-mediated T-cell death is a requisite mechanism underlying transplant tolerance.

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