Mechanism of the inhibitory effects of leukocyte immunoglobulin-like receptor B4 (LILRB4) on monocytes

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Copyright: Lu, Hao Kim
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Abstract
The leukocyte immunoglobulin-like receptor (LILR) B4 belongs to a family of activating and inhibitory cell surface receptors that are increasingly recognised as key regulators of leukocyte functions. LILRB4 is an inhibitory molecule that is highly expressed on the surface of monocytes and macrophages. It is believed to inhibit leukocyte activation through the recruitment of phosphatases to its ITIM-containing cytoplasmic tail. However, there is no comprehensive data that elucidate the underlying mechanisms of LILRB4-mediated inhibitory effects and signalling in vitro and in vivo. This is in part due to lack of in depth investigation of the effects of LILRB4 in vitro. The first part of the project showed that LILRB4 is a potent inhibitor of FcγRI-mediated TNFα production in monocyte. Furthermore, LILRB4 was shown to selectively down-regulate key protein tyrosine kinases such Lck, Syk, LAT and Erk that are involved in the secretory functions of monocytes, but not the cytoskeletal protein α-actinin-4. Furthermore, this study is the first to shows that LILRB4 utilise multiple phosphatases including a novel SHP-1-like phosphatase for its inhibitory functions. The second part of this project investigated whether LILRB4 also modulate other key monocyte/macrophage functions, notably Fc receptor-mediated phagocytosis and bactericidal activity. While LILRB4 is a potent inhibitor of FcγRI-mediated pro-inflammatory cytokine production, the results in this chapter show that it has only limited effect on phagocytosis and bactericidal functions, indicating that it is a selective inhibitory receptor of the secretory functions of monocytes. Finally, the last part of this project focused on the development of novel methodologies for the identification and characterisation of LILRB4 ligand(s). Using a recombinant LILRB4 protein generated from a mammalian cell system, this chapter shows that the ligand(s) of LILRB4 is expressed on the surface of PBMCs from healthy individuals. For the first time, the dissociation constant (Kd) of this interaction was also determined to be 29 nM, indicating a moderately high affinity receptor-ligand interactions between LILRB4 and its ligand(s). Taken together, this work demonstrated that LILRB4 is a potent yet selective inhibitor of key monocyte functions and has provided some preliminary data on the characteristics of the natural ligand(s) of LILRB4.
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Author(s)
Lu, Hao Kim
Supervisor(s)
Tedla, Nicodemus
Bryant, Katherine
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Publication Year
2011
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Thesis
Degree Type
PhD Doctorate
UNSW Faculty
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