Mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2-dependent pathways are essential for CD8+ T cell-mediated airway hyperresponsiveness and inflammation.
BACKGROUND
Ligation of the leukotriene B(4) (LTB(4)) receptor 1 on effector memory CD8(+) T cells by LTB(4) is important for the recruitment of CD8(+) T cells into the airways, which appears central to the induction of airway hyperresponsiveness (AHR) and allergic inflammation. Phosphorylation of extracellular signal-regulated kinase (ERK) is important in activation and cytokine production from many cell types.


OBJECTIVE
The roles of ERKs in effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR were determined.


METHODS
Effector CD8(+) T cells were generated from OVA(257-264) (SIINFEKL) peptide-primed mononuclear cells from OT-1 mice. The effects of U0126, an ERK inhibitor, on effector CD8(+) T-cell function and on CD8(+) T cell-mediated AHR and allergic inflammation were examined.


RESULTS
Pretreatment of effector CD8(+) T cells with U0126 suppressed anti-CD3/anti-CD28-induced ERK1/2 phosphorylation and cytokine production, but did not affect LTB(4)-induced Ca(2+) mobilization or chemotaxis. Adoptive transfer of U0126-treated CD8(+) T cells into sensitized mice before secondary allergen challenge resulted in significant decreases in AHR, eosinophilic inflammation, goblet cell metaplasia, and IL-5 and IL-13 levels in bronchoalveolar lavage fluid of recipient mice. The number of transferred CD8(+) T cells accumulating in bronchoalveolar lavage fluid or lungs was unaffected by treatment.


CONCLUSIONS
ERK1/2-dependent pathways are essential for the effector functions of CD8(+) T cells, including T(H)2 cytokine production, allergic inflammation, and development of AHR. Inhibition of ERK1/2 signaling has potential therapeutic benefit in preventing CD8(+) T cell-mediated AHR.
Ohnishi
Hiroshi
H
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, CO, USA.
Takeda
Katsuyuki
K
Domenico
Joanne
J
Lucas
Joseph J
JJ
Miyahara
Nobuaki
N
Swasey
Christina H
CH
Dakhama
Azzeddine
A
Gelfand
Erwin W
EW
D019264:Adoptive Transfer; D000485:Allergens / Q000276:immunology / Q000494:pharmacology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002070:Butadienes / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects / Q000276:immunology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004804:Eosinophils / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020397:Goblet Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007156:Immunologic Memory / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007975:Leukotriene B4 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D008679:Metaplasia / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D018102:Receptors, Leukotriene B4 / Q000276:immunology / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000201:enzymology / Q000276:immunology / Q000473:pathology
D000485:Allergens; D002070:Butadienes; D004791:Enzyme Inhibitors; D009570:Nitriles; D018102:Receptors, Leukotriene B4; C113580:U 0126; D007975:Leukotriene B4; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium