Inhibition of allogeneic cytotoxic T cell (CD8+) proliferation via polymer-induced Treg (CD4+) cells

T cell-mediated immune rejection remains a barrier to successful transplantation. Polymer-based bioengineering of cells may provide an effective means of preventing allorecognition and the proliferation of cytotoxic (CD8+) T lymphocytes (CTL). Using MHC-disparate murine splenocytes modified with succinimidyl valerate activated methoxypoly(ethylene glycol) [SVA-mPEG] polymers, the effects of leukocyte immunocamouflage on CD8+ and CD4+ alloproliferation and T regulatory (Treg) cell induction were assessed in a mixed lymphocyte reaction (MLR) model. Polymer-grafting effectively camouflaged multiple leukocyte markers (MHC class I and II, TCR and CD3) essential for effective allorecognition. Consequent to the polymer-induced immunocamouflage of the cell membrane, both CD8+ and CD4+ T cell alloproliferation were significantly inhibited in a polymer dose-dependent manner. The loss of alloproliferation correlated with the induction of Treg cells (CD4+CD25+Foxp3+). The Tregs, surprisingly, arose primarily via differentiation of naive, non-proliferating, CD4+ cells. Of biologic importance, the polymer-induced Treg were functional and exhibited potent immunosuppressive activity on allogeneic CTL proliferation. These results suggest that immunocamouflage-mediated attenuation of alloantigen-TCR recognition can prevent the tissue destructive allogeneic CD8+ T cell response, both directly and indirectly, through the generation/differentiation of functional Tregs. Immunocamouflage induced tolerance could be clinically valuable in attenuating T cell-mediated transplant rejection and in the treatment of autoimmune diseases.