Differential signal transduction, membrane trafficking, and immune effector functions mediated by FcgammaRI versus FcgammaRIIa.
Receptors for the fragment crystallizable region of immunoglobulin-G (FcgammaRs) 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 2 human Fc-receptors, FcgammaRI and FcgammaRIIa. Activation of FcgammaRI results in a novel signaling cascade that links phospholipase D1 to sphingosine kinase-1 in U937 cells and primary human monocytes. This induces the expression of proinflammatory mediators and is associated with trafficking of immune complexes into human leukocyte antigen-DM positive antigen-processing compartments coupled with improved MHC class II-mediated antigen presentation to T lymphocytes. In contrast, activation of FcgammaRIIa elicits signaling through phospholipase Cgamma1, resulting in increases in intracellular calcium, activation of nicotinamide adenine dinucleotide phosphate-oxidative burst, and differential membrane trafficking combined with impaired antigen presentation and proinflammatory 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 proinflammatory signaling and antigen presentation, versus the maintenance of immunologic homeostasis through the noninflammatory clearance of immune complexes.
Department of Microbiology, National University of Singapore, Singapore.
Xilei
X
Dai
Manikandan
M
Jayapal
Hwee Kee
HK
Tay
Renji
R
Reghunathan
Gen
G
Lin
Chien Tei
CT
Too
Yan Ting
YT
Lim
Soh Ha
SH
Chan
D Michael
DM
Kemeny
R Andres
RA
Floto
Kenneth G C
KG
Smith
Alirio J
AJ
Melendez
Paul A
PA
MacAry
D017951:Antigen Presentation / Q000276:immunology; D020013:Calcium Signaling; D002462:Cell Membrane / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D018384:Oxidative Stress; D051966:Phospholipase C gamma / Q000378:metabolism; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D021381:Protein Transport; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D016207:Cytokines; D007527:Isoenzymes; D017452:Receptors, IgG; D011493:Protein Kinase C; D051966:Phospholipase C gamma