Differential regulation of CD8 T cell responses by surface and endosomal TLRs (INC6P.347)

Abstract

Abstract Sensing of pathogen/pathogen derived products through Toll like receptors (TLRs) induces dendritic cell (DC) maturation characterized by the expression of co-stimulatory molecules and secretion of pro-inflammatory cytokines. These two signals play a critical role in activation and differentiation of CD4 T cells. However, since the role of TLRs in the regulation of CD8 T cell responses is not clear we sought to address their role in this process. Our results show that although most TLRs induce the CD8 T cell proliferation in-vitro, there are significant differences in the CD8 T cell priming in-vivo to pathogenic infections. Endosomal TLRs (TLR3 and TLR9) that sense nucleic acids show a remarkable ability to induce CD8 T cell responses. However, surface TLRs (TLR2 and TLR4) that sense bacterial ligands were incapable of inducing CD8 T cell responses. Moreover, surface TLRs dominantly suppress the CD8 T cell activation induced by endosomal TLRs. Cell migration experiments show that surface TLR activation skewed lymphoid (CD11c+, CD8+) to myeloid (CD11c+, CD11b+ CD8-) DC populations in the draining lymph nodes. We also found that DC intrinsic TLR2 and TLR4, acting in a MyD88-dependent manner, altered the ability of DCs to prime CD8 T cells. In summary, our results demonstrate that bacterial co-infection dampens the ability of DCs to induce efficient anti-viral CD8 T cell responses.