In the context of transplantation, activation of innate immunity by endogenous or exogenous Toll-like receptor (TLR) ligands boosts alloreactive T cell response and is considered as a hurdle for tolerance induction. On the other hand, sustained or repeated exposure to TLR ligands results in suppression of the synthesis of inflammatory mediators whereas production of anti-inflammatory cytokines is preserved, a process named TLR desensitization. We recently observed that desensitization to bacterial lipopolysaccharide (LPS) - a prototypic TLR4 ligand - before transplantation may improve allograft survival. This was associated with accumulation of myeloid CD11b+GR1+ cells endowed with suppressive capacities. The regulatory activity of these CD11b+GR1+ cells depends on heme oxygenase-1 and interleukin-10. The aim of this project is to decipher the links between LPS-desensitization, emergence of CD11b+GR1+ cells and suppression of alloimmune responses, with the ultimate goal to exploit TLR signals as negative immunoregulators. Another approach consists in evaluating the role of the cholinergic anti-inflammatory pathway in the modulation of the innate and adaptive branches of the alloimmune response. These questions will be addressed using a panel of cellular and molecular biology approaches and in vivo imaging techniques.