Type 1 diabetes (T1D) is a complex and multifactorial disease. Its pathogenesis is characterized by a pro-inflammatory status that can be found early in subjects at risk. β-Cell inflammation is mediated by pro-inflammatory cytokines but also by pathogen and danger associated molecular patterns (PAMP and DAMP). These exogenous and endogenous ligands are recognized by pattern recognition receptors (PRR), expressed by β-cells and immune cells. This work explored, in a murine model of T1D, the implication of Toll-like receptor 4 (TLR4) in the development of T1D, its role in the response of autoreactive T lymphocytes and the mechanism that regulates its expression in these cells. This work demonstrated that TLR4 is involved in the pathogenesis of autoimmune diabetes in NOD mice and it mediates the activation of CD4+ T lymphocytes. TLR4-mediated effect on CD4+ T lymphocyte is dependant of Macrophage Migration Inhibitory Factor (MIF). In addition, MIF also inhibits TCR/CD3-mediated activation and thus appears to be major regulator of T cell response.