TIM3 promotes cross-presentation dependent CD8+ T cell responses to soluble antigen and influenza 4814

Abstract Description T cell immunoglobulin and mucin domain 3 (TIM3) promotes uptake of apoptotic cells and suppresses cytosolic DNA sensing and inflammasome activation in type 1 conventional dendritic cells (DC1), which are specialized for cross-presentation. Studies examining the effect of TIM3 on cross-presentation are conflicting. We sought to further define the effect of TIM3 on cross-presentation of soluble antigen and in the context of influenza. CFSE-labeled OT-I were adoptively transferred into WT and TIM3 deficient (KO) mice. TLR3 ligand polyI:C and soluble ovalbumin (OVA) were given intravenously 24 hours later. Flow cytometry revealed a 3.8-fold reduction in the frequency of splenic OT-I in KO compared to WT (0.03 vs 0.12% of live singlets, p = 0.0103) as well as a 2-fold reduction in the number of CD11a+CD44+ OT-I (1.8 x103 vs 3.5 x103, p = 0.0107). Using in vitro assays, we found that classical presentation of soluble antigen is intact in KO DC1, but these cells have a specific defect in cross-presentation associated with reduced antigen degradation. We next infected mice with deletion of TIM3 specifically from conventional DC (cKO) with influenza A virus (IAV)-NP142t, which does not productively infect DC. Antigen experienced CD8+ T cells were reduced 3-fold in cKO compared to controls at 5 days post infection (7x103 vs 2.3x104, p = 0.0054). Our data suggest TIM3 promotes cross-presentation of soluble antigen and in the context of influenza. Funding Sources Supported by NIH R01HL148758; NIH T32AI007485; NIAID K08AI113083 Topic Categories Antigen and Dendritic Cell Processing, Presentation, and Biology (AGDC)