Antigen-Encoding Bone Marrow Terminates Islet-Directed Memory CD8+ T-Cell Responses to Alleviate Islet Transplant Rejection

Miranda A. Coleman, Claire F. Jessup, Jennifer A. Bridge, Nana H. Overgaard, Daniella Penko, Stacey Walters, Danielle J. Borg, Ryan Galea, Josephine M. Forbes, Ranjeny Thomas, Patrick T.C. Coates, Shane T. Grey, James W. Wells, Raymond J. Steptoe

Islet-specific memory T cells arise early in type 1 diabetes (T1D), persist for long periods, perpetuate disease and are rapidly reactivated by islet transplantation. As memory T cells are poorly controlled by 'conventional' therapies, memory T-cell mediated attack is a substantial challenge in islet transplantation and this will extend to application of personalized approaches using stem-cell derived replacement β cells. New approaches are required to limit memory autoimmune attack of transplanted islets or replacement β cells. Here we show that transfer of bone marrow encoding cognate antigen directed to dendritic cells, under mild, immune-preserving conditions inactivates established memory CD8(+) T-cell populations and generates a long-lived, antigen-specific tolerogenic environment. Consequently, CD8(+) memory T cell-mediated targeting of islet-expressed antigens is prevented and islet graft rejection alleviated. The immunological mechanisms of protection are mediated through deletion and induction of unresponsiveness in targeted memory T-cell populations. The data demonstrate that hematopoietic stem cell-mediated gene therapy effectively terminates antigen-specific memory T-cell responses and this can alleviate destruction of antigen-expressing islets. This addresses a key challenge facing islet transplantation and importantly, the clinical application of personalized β-cell replacement therapies using patient-derived stem cells.