Regulation of systemic lupus via ICOS triggering by mononuclear phagocytes and B cells
Final Report Abstract
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 which 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. Surprisingly, 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 signaling activity of the PI3K-Akt pathway, thereby facilitating T cell accrual. These findings provide new insights into local mechanisms that sustain organ inflammation in lupus.
Publications
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“Local Triggering of the ICOS Coreceptor by CD11c+ Myeloid Cells Drives Organ Inflammation in Lupus”, Immunity, vol. 42, no. 3, pp. 552–65, 2015
L. L. Teichmann, J. L. Cullen, M. Kashgarian, C. Dong, J. Craft, and M. J. Shlomchik
