PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is characterized by hyperactivation of T cells, B cells and dendritic
cells (DCs), production of autoantibodies to nucleic acid-associated and other self-molecules, and immune
complex-mediated inflammatory damage in multiple organs. Mechanistic assessments in both mouse
models and humans have implicated innate immune pathways of nucleic acid sensing in lupus
pathogenesis, particularly Toll-like receptor (TLR) activation in B cells and plasmacytoid dendritic cells
(pDCs), production of type I interferons, and expression of an interferon-inducible gene signature often
correlating with disease activity. Additional studies including by our laboratory have shown that pathogenic
TLR responses in systemic autoimmunity require the participation of the peptide/histidine transporter
SLC15A4, suggesting that inhibition of this transporter may be an effective therapeutic approach. Very
recent studies, however, suggested that SLC15A4 does not act as a transporter but rather as binding
partner of TASL, which in turn facilitates TLR signaling. Thus, the focus of this proposal is to define
mechanistically how SLC15A4 and TASL contribute to TLR activation. For this we will use a novel TASL-
deficient mouse model that will allow to separate the SLC15A4 role as a transporter vs. its role as a platform
that facilitates recruitment of TASL. Crucially, these studies will clarify if pharmacologic inhibition of the
SLC15A4 transporter activity is an appropriate strategy, or if instead targeting TASL would be a better
approach to reduce inflammatory responses in lupus and other autoimmune conditions.
