Mycobacterial lipoarabinomannans modulate cytokine production in human T helper cells by interfering with raft/microdomain signalling.
Lipoarabinomannans (LAMs) are major lipoglycans of the mycobacterial envelope and constitute immunodominant epitopes of mycobacteria. In this paper, we show that mannose-capped (ManLAM) and non-mannose-capped (PILAM) mycobacterial lipoglycans insert into T helper cell rafts without apparent binding to known receptors. T helper cells modified by the insertion of PILAM responded to CD3 cross-linking by decreasing type 1 (IL-2 and IFN-gamma) and increasing type 2 (IL-4 and IL-5) cytokine production. Modification by the mannose-capped ManLAMs had similar, but more limited effects on T helper cell cytokine production. When incorporated into isolated rafts, PILAMs modulated membrane-associated kinases in a dose-dependent manner, inducing increased phosphorylation of Src kinases and Cbp/PAG in Th1 rafts, while decreasing phosphorylation of the same proteins in Th2 rafts. Mycobacterial lipoglycans thus modify the signalling machineries of rafts/microdomains in T helper cells, a modification of the membrane organization that eventually leads to an overall enhancement of type 2 and inhibition of type 1 cytokine production.
Shabaana
A K
AK
Department of Pathology and Immunology, Centre médical universitaire, University of Geneva Medical School, 1 rue Michel-Servet, 1211, Geneva 4, Switzerland.
Kulangara
K
K
Semac
I
I
Parel
Y
Y
Ilangumaran
S
S
Dharmalingam
K
K
Chizzolini
C
C
Hoessli
D C
DC
D001483:Base Sequence; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008358:Mannose / Q000737:chemistry / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009161:Mycobacterium / Q000737:chemistry / Q000276:immunology*; D015398:Signal Transduction; D018417:Th1 Cells / Q000737:chemistry / Q000276:immunology*; D018418:Th2 Cells / Q000737:chemistry / Q000276:immunology*
D016207:Cytokines; D007378:Interleukins; D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; C050016:lipoarabinomannan; D008358:Mannose