The SLC15A4-TASL complex is essential for lupus development in mice.

Abstract

Nucleic acid sensing by endolysosomal Toll-like receptors is critically involved in systemic lupus erythematosus (SLE) and related autoimmune diseases. Downstream of TLR7, TLR8, and TLR9, the SLE-associated SLC15A4-TASL complex selectively mediates IRF5 activation, while being dispensable for NF-κB and MAPK pathways. Here, we show that the SLC15A4-TASL signaling axis is broadly required for disease development and pathogenesis across three complementary genetic SLE models, reflecting different etiologies. Genetic ablation of <i>Tasl</i> (<i>Tasl</i>^KO) and its paralogue <i>Tasl2</i> (<i>Tasl</i>^DKO) ameliorated or fully prevented autoimmune manifestations resulting from <i>Fas</i>^lpr loss of function, respectively. Furthermore, SLC15A4-TASL complex deficiency was sufficient to protect from disease, including splenomegaly, immune activation, and autoantibody formation, driven by the patient-derived <i>Tlr7</i>^Y264H gain-of-function mutation, even in the presence of functional NF-κB and MAPK responses. Last, <i>Tasl</i>^DKO splenocyte transfer into lymphopenic <i>Dnase1l3</i>-deficient mice demonstrated that protection extends to DNA-driven autoimmunity, in which TLR7 and TLR9 act redundantly, strongly supporting a B cell-intrinsic role. Notably, SLC15A4-TASL complex deficiency blunted the generation of pathogenic age-associated B cells in all three autoimmune models as well as in aged animals. Collectively, these data demonstrate the central role of the SLC15A4-TASL complex in SLE, supporting its potential as therapeutic target.