TLR7/8 Differentially Regulates Fcγ Receptor Expression and Function.

Abstract 3594

Poster Board III-531

Activation of Toll-like Receptors (TLR) 7 and 8 by engineered agonists has been shown to aid in combating viruses and tumors, and such compounds are in clinical use. We examined the effect of one agonist, R848, on monocyte Fcγ receptor (FcγR) expression. Results showed that overnight treatment with R848 increased expression of FcγRI, FcγRIIa and the common γ-subunit. Surprisingly, expression of the inhibitory FcγRIIb was almost completely abolished. We then treated bone marrow-derived macrophages from Wild-type, TLR7^−/−, MyD88^−/−, TRIF^−/− and Cryopyrin^−/− mice with R848 to test which pathway influenced FcγR expression. FcγR expression remained unchanged in TLR7^−/− and MyD88^−/− mice, suggesting that the TLR7 / MyD88 pathway was required. In order to test the functional effect of R848 treatment on monocyte FcγR, we treated monocytes with R848 and then co-incubated them with Rituximab-coated Raji B-cell lymphoma cells. Flow cytometric analysis showed that the treated monocytes led to a significantly greater decrease in intact antibody-coated Raji cells. Further, R848 treatment synergistically increased monocyte FcγR-mediated cytokine production. In conclusion, there are both regulatory and functional links between the TLR7/8 and FcγR pathways. This has implications for both antitumor immunotherapy and autoimmune diseases.