Environment has both pathogenic and protective roles in the determination of autoimmune disease development, possibly through infectious agents. TLR2 has the capability to recognize the widest range of PAMPs, and it is important for the recognition of mycobacteria and gram-positive bacteria. Here we review recent information showing that TLR2 ligands, its signaling machinery and the effects of its engagement on T cell polarization and differentiation, all play a decisive role in experimental models of autoimmunity. Thus, we propose that engagement of TLR2 is an important crossroads between encounter with bacteria and development of self-reactive diseases.