A single non-synonimous polymorphism of TLR2 modifies a binding site for small ligands, alters Th1/Th17 and Treg polarization of T cells and modifies clinic outcome of EAE

We previously reported that a SNP of Tlr2 (82Met/Ile of B6 versus SJL) expressed on T cells regulates the mobilization of T cells from lymph nodes (LN). We show here that SNP Ile82Met results in a modification of a binding site for small ligands. Microarray analysis showed minimal (if any) differences between murine LN cells expressing one or both SNP of Tlr2, early after immunization with proteolipid protein peptide 139-151 (p139); however the p139-response displayed a relevant bias towards Th1/Th17 both at the level of cytokine secretion and of mRNA, while at the same time showed antigen-dependent expansion of CD4+ CD25+ FoxP3+ cells and mRNA. Accordingly, mRNAs specific for cytokines directing polarization to Th1/Th17 and Treg were increased in mice with only 82MetSNP. It seems unlikely that this SNP affects the dimerization of Tlr2 with Tlr1 or Tlr6, in fact in the SJL strain Tlr2 engagement does not decrease the Ag-driven expansion of Treg cells. Taken together these data support the hypothesis that the modification of Th polarization by Tlr2 haplotype depends on Tlr2 expressed by the Antigen-presenting cells, in contrast with the dominant role that Tlr2 expressed on T cells plays in the regulation of mobility. Mice with only 82Met SNP of Tlr2 also affected the outcome of EAE, showing a more severe relapsing-remitting disease if compared with mice with both SNPs. Thus, these data propose a model in which Tlr2 ligands binding far from the classic binding site for PAM(s) can regulate autoimmunity