Toll-like receptor ligands differentially activate human innate immune system and distinctively enhance antigen-specific T cell response to vaccination in humanized mice (VAC4P.1105)

Abstract

Abstract TLR-Ls represent a new class of novel vaccine adjuvant. However, their immunologic effects in humans remain poorly defined in vivo. Here we investigated how TLR-Ls stimulated human immune system in vivo and their application as immune adjuvant using the humanized mouse model. To our surprise, we found that various TLR-Ls (CpG-A/CpG-B/CpG-C, R848, R837, MPLA and Poly I:C) stimulated human cytokines very differently in humanized mice in vivo compared to that in human PBMCs in vitro. The different in vivo response to TLR-Ls was not due to the improper development of human immune cells in vivo because splenocytes from humanized mice showed identical responses as human PBMC in vitro to various TLR-Ls. Importantly, the human innate immune response to specific TLR-Ls in humanized mice in vivo was different from that reported in C57/BL6 mice, but similar to that reported in nonhuman primates. Furthermore, we showed that distinct TLR-Ls differentially activated and mobilized human pDCs, mDCs and monocytes in different organs in vivo. Finally, we showed that Poly I:C and R848 were superior to CpG-B, for enhancing antigen specific CD4+ and CD8+ T cell responses to a CD40-targeting HIV candidate vaccine in humanized mice, which correlated with their ability to activate human CD141+ mDCs and IL-12 induction. Thus, we conclude that humanized mice serve as a highly relevant model to evaluate and rank the human immunologic effects of novel adjuvants in vivo prior to testing in humans.