Local Triggering of the ICOS Coreceptor by CD11c+ Myeloid Cells Drives Organ Inflammation in Lupus

The inducible T cell costimulator (ICOS) is a potent promoter of organ inflammation in murine lupus. ICOS stimulates T follicular helper cell differentiation in lymphoid tissue, suggesting that it might drive autoimmunity by enhancing autoantibody production. Yet the pathogenic relevance of this mechanism remains unclear. It is also unknown whether other ICOS-induced processes might contribute to lupus pathology. Here we show that selective ablation of ICOS ligand (ICOSL) in CD11c+ cells, but not in B cells, dramatically ameliorates kidney and lung inflammation in lupus-prone MRL.Faslpr mice. Autoantibody formation was largely unaffected by ICOSL deficiency in CD11c+ cells. However, ICOSL display by CD11c+ cells in inflamed organs had a nonredundant role in protecting invading T cells from apoptosis by elevating activity of the PI3K-Akt signaling pathway, thereby facilitating T cell accrual. These findings reveal a mechanism that locally sustains organ inflammation in lupus. •ICOSL deficiency in CD11c+ myeloid cells attenuates organ inflammation in lupus•Autoantibody production is largely unaffected by the loss of ICOSL in CD11c+ cells•CD11c+ cells through ICOSL locally protect organ-infiltrating T cells from apoptosis•ICOSL display by CD11c+ myeloid cells promotes PI3K-Akt signaling in invading T cells How the inducible T cell costimulator (ICOS) promotes organ inflammation in lupus is unclear. Shlomchik and colleagues demonstrate that in inflamed kidneys infiltrating T cells require ICOS stimulation by local CD11c+ myeloid cells for their survival, an effect mediated by PI3K-Akt signaling.