Submitted October 17, 2008
Accepted April 22, 2009
Differential signal transduction, membrane trafficking and immune effector functions mediated by Fc
RI versus FcRIIa
Xilei Dai, Manikandan Jayapal, Hwee Kee Tay, Renji Reghunathan, Gen Lin, Chien Tei Too, Yan Ting Lim, Soh Ha Chan, D. Michael Kemeny, R. Andres Floto, Kenneth G.C. Smith, Alirio J. Melendez, and Paul A. MacAry*
Department of Microbiology, National University of Singapore, Singapore, Singapore
Department of Physiology, National University of Singapore, Singapore, Singapore
Department of Medicine/CIMR University of Cambridge, Cambridge, United Kingdom
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom
* Corresponding author; email: micpam{at}nus.edu.sg.
Receptors for the fragment crystallizable region of immunoglobulin-G (Fc
Rs) play an important role in linking the humoral and cellular arms of the immune response. In this study we present a comprehensive functional comparison of two human Fc-receptors, FcRI and FcRIIa. Activation of FcRI results in a novel signalling cascade that links phospholipase D1 to sphingosine kinase-1 in U937 cells and primary human monocytes. This induces the expression of pro-inflammatory mediators and is associated with trafficking of immune complexes into HLA-DM positive antigen-processing compartments coupled with improved MHC class-II mediated antigen presentation to T-lymphocytes. In contrast, activation of FcRIIa elicits signalling through phospholipase C1, resulting in increases in intracellular calcium, activation of NADPH-oxidative burst, and differential membrane trafficking combined with impaired antigen presentation and pro-inflammatory cytokine expression. These data provide a mechanistic insight into the disparate activities associated with Fc-receptors in immunity; namely, reinforcement of immune responses through stimulation of pro-inflammatory signalling and antigen presentation, versus the maintenance of immunological homeostasis through the non-inflammatory clearance of immune complexes.
