- Toll Like Receptors (TLRs) are major facilitators of the innate immune response. Although the structure and function of TLRs are well studied, the role of their transmembrane domain has not been fully understood. Here we show that peptides based on the TM domain of TLR2 and TLR1/6 specifically inhibit TLR2 activation. These peptides inhibited TNFα secretion by mouse macrophages after lipotechoic acid (LTA, the cell wall of Gram-positive bacteria) activation, while no effect was seen on TLR4 activation by lipopolysacharide (LPS, the cell wall of Gram-negative bacteria). FRET analysis and self assembly assays revealed that these TM peptides are capable of interacting with each other, favoring hetero- rather than homo-dimerisation. Finally, a selected TLR2 TM peptide was able to rescue up to 60% of mice affected by an otherwise lethal acute systemic inflammation driven by hyperactivation of TLR2.