Weiming Yuan

PIBBS MENTOR

Associate Professor
Molecular Microbiology and Immunology
Keck School of Medicine

Research Topics

  • CD1d and NKT antigen presentation system in anti-viral and anti-cancer immunity
  • Evasion of NKT cell function by herpes viruses
  • Humanizing mice for studying CD1d/NKT system in anti-cancer immunity

Research Overview

NKT cells are an unconventional subset of T cells co-expressing T-cell receptor (TCR) and typical surface receptors for NK cells. In contrast to conventional adaptive T cells and B cells, NKT cells have features of both innate and adaptive arms of immune systems. Over the last several decades, NKT cells have been found to influence diverse immune responses, including immunity to infectious diseases and tumor, autoimmune diseases and allergies. Although the exact function of NKT cells during various immune responses remains elusive, recent studies have suggested that NKT cells may have been evolved primarily for their role in antimicrobial immune responses. Most NKT cells express identical or similar T cell receptors and are often called invariant NKT cells or iNKT cells. Distinct from conventional CD4+ and CD8+ T cells, iNKT cells can be activated by either exogenous or endogenous lipid ligands. In some bacterial infection, bacteria-derived exogenous lipid ligands can be directly recognized by iNKT cell TCR. In most other bacterial or viral infection, dendritic cell-derived cytokines and endogenous lipid ligands are sufficient to activate iNKT cells. During immune responses, NKT cells are rapidly activated to produce cytokines such as g-interferon (IFN-g) and IL-4, and their activation plays a key role in the development and regulation of adaptive immune responses to microbes.

Due to the critical antiviral roles of NKT cells, herpes viruses have evolved strategies to antagonize this function. In vivo, NKT cells are mostly activated by lipid antigen presentation by CD1d. Previously, our studies have shown that herpes simplex virus-1 (HSV-1), a common herpes virus in humans, has evolved to down-regulate CD1d expression in antigen-presenting cells and thereby inhibiting NKT cell activation (Yuan, W. et al., Nature Immunol. 2006, 7, 835-842). Dissecting the molecular mechanism of HSV-1 evasion of CD1d antigen presentation and NKT cell function will provide novel targets for antiviral designs to improve the care for patients already latently infected with HSVs. Furthermore to break down the viral immune evasion mechanism will help to improve the immunogenecity and therefore the protection efficiency of vaccine candidates to prevent new infections. We have recently identified a HSV-1 protein kinase, US3, that collaborates with viral glycoprotein B to down-regulate CD1d expression in antigen presenting cells by suppressing CD1d recycling (Rao, P. et al., J. Virol. 2011, 85: 8093-8104; Ran, X. et al., J. Virol. 2015, 89: 6646-6655). Currently we are pursuing how US3, through its kinase activity, modulates CD1d recycling pathway at both molecular and cellular levels. Remarkably, while US3-difficient virus grows well in vitro, its replication is severely attenuated in vivo, suggesting that the evasion of the CD1d-restricted NKT cell function plays a critical role in viral pathogenesis.

An emerging research field in my lab is human-specific CD1d/NKT antigen presentation. Despite a high degree of conservation, subtle but important differences exist between the CD1d antigen presentation pathways of humans and mice. These differences may account for the minimal success of natural killer T (NKT) cell-based antitumor therapies in human clinical trials, which contrast strongly with the powerful antitumor effects in conventional mouse models. In order to study human-specific CD1d antigen presentation pathway in vivo, we have recently generated novel mouse models with CD1d/NKT system humanized (Wen, X., et al., Proc. Natl. Acad. Sci. USA 2013, 110: 2963-2968; Wen, X., et al., J. Immunol. 2015, 195: 1459-1469). Characterization of these new models and application of the models to cancer immunotherapy research are currently ongoing.