Uncoupling of T-cell effector functions by inhibitory killer immunoglobulin-like receptors.
Killer immunoglobulin-like receptors (KIRs) are a family of regulatory cell-surface molecules expressed on natural killer (NK) cells and memory T-cell subsets. Their ability to prevent the formation of an activation platform and to inhibit NK cell activation is the basis of the missing self model of NK cell function. The benefits of KIR expression for T-cell biology are unclear. We studied how KIR2DL2 regulates T-cell function. Engagement of KIR2DL2 by the ligand human leukocyte antigen (HLA)-Cw3 did not affect conjugate formation between CD4(+)KIR2DL2(+) T cells and superantigen-pulsed target cells or the development of mature immune synapses with lipid rafts. KIR2DL2 and the corresponding HLA-C ligand were initially recruited to the peripheral supramolecular activation cluster (pSMAC). Consequently, KIR2DL2 engagement did not inhibit the phosphorylation of early signaling proteins and T-cell-receptor (TCR)-mediated cytotoxicity or granule exocytosis. After 15-30 minutes, KIR2DL2 moved to the central supramolecular activation cluster (cSMAC), colocalizing with CD3. TCR synapses dissociated, and phosphorylated phospholipase C (PLC)-gamma1, Vav1, and extracellular signal-regulated kinase 1/2 (ERK1/2) were reduced 90 minutes after stimulation. Gene array studies documented that the inhibition of late signaling events by KIR2DL2 affected transcriptional gene activation. We propose that KIRs on memory T cells operate to uncouple effector functions by modifying the transcriptional profile while leaving granule exocytosis unabated.
Kathleen B. and Mason I Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Gabriella
G
Henel
Karnail
K
Singh
Dapeng
D
Cui
Sergey
S
Pryshchep
Won-Woo
WW
Lee
Cornelia M
CM
Weyand
Jörg J
JJ
Goronzy
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation; D003602:Cytotoxicity, Immunologic; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology; D021962:Membrane Microdomains; D021381:Protein Transport; D011971:Receptors, Immunologic / Q000276:immunology / Q000502:physiology*; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D015398:Signal Transduction / Q000276:immunology*; D018089:Superantigens / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D015533:Transcriptional Activation
C515077:KIR2DL2 protein, human; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D054343:Receptors, KIR2DL2; D018089:Superantigens