Autophagy: basic principles and relevance to transplant immunity.

Autophagy developed into a rapidly expanding field detailing its molecular mechanism and relevance in health and disease. Autophagy is an evolutionarily conserved process that summarizes a pathway in which intracellular material is degraded within the lysosome and where the macromolecular constituents are recycled. This "self-eating" process was originally described in a cell under starvation but now numerous studies established autophagy as a cellular response to stress. As a consequence, the autophagy machinery interfaces with most cellular stress-response pathways, including those involved in controlling immune response and inflammation. Autophagy also influences adaptive immunity through its effect on antigen presentation, naïve T cell repertoire selection and homeostasis and TH cell polarization. Data are emerging that dysregulated autophagy has an impact on human pathologies including infectious diseases, cancers, aging and neurodegenerative conditions. This review focuses on recent findings elucidating the ability of autophagy to be of significance in the transplant setting.

Costimulatory blockade-induced allograft survival requires Beclin1.

Autophagy is required for T cell homeostasis and activation-induced T cell expansion. Whether autophagy participates in tolerance induction to foreign antigens, including allografts, is unknown. We tested the role of an essential autophagy protein, Beclin1, in heart transplant survival in mice. We observed that long-term allograft survival induced by donor-specific transfusion plus anti-CD154 mAb required homozygous lymphocyte expression of Beclin1. Following adoptive transfer into allogeneic recipients, autophagy-deficient, Beclin1 heterozygous effector T cells (Teffs) exhibited enhanced proliferation with diminished cell death and increased production of interferon gamma. Whereas the induction and function of regulatory T cells (Tregs) in Beclin1 heterozygous mice were normal, Teffs from these mice were resistant to Treg-mediated suppression. Our findings identify a requisite role for Beclin1 in facilitating Teff death during tolerance induction.