Crucial role of the interleukin 1 receptor family member T1/ST2 in T helper cell type 2-mediated lung mucosal immune responses.
T1/ST2 is an orphan receptor of unknown function that is expressed on the surface of murine T helper cell type 2 (Th2), but not Th1 effector cells. In vitro blockade of T1/ST2 signaling with an immunoglobulin (Ig) fusion protein suppresses both differentiation to and activation of Th2, but not Th1 effector populations. In a nascent Th2-dominated response, anti-T1/ST2 monoclonal antibody (mAb) inhibited eosinophil infiltration, interleukin 5 secretion, and IgE production. To determine if these effects were mediated by a direct effect on Th2 cells, we next used a murine adoptive transfer model of Th1- and Th2-mediated lung mucosal immune responses. Administration of either T1/ST2 mAb or T1/ST2-Ig abrogated Th2 cytokine production in vivo and the induction of an eosinophilic inflammatory response, but failed to modify Th1-mediated inflammation. Taken together, our data demonstrate an important role of T1/ST2 in Th2-mediated inflammatory responses and suggest that T1/ST2 may prove to be a novel target for the selective suppression of Th2 immune responses.
Coyle
A J
AJ
Department of Biology, Inflammation Division, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA. coyle@mpi.com
Lloyd
C
C
Tian
J
J
Nguyen
T
T
Erikkson
C
C
Wang
L
L
Ottoson
P
P
Persson
P
P
Delaney
T
T
Lehar
S
S
Lin
S
S
Poisson
L
L
Meisel
C
C
Kamradt
T
T
Bjerke
T
T
Levinson
D
D
Gutierrez-Ramos
J C
JC
D000485:Allergens; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019556:COS Cells; D002454:Cell Differentiation; D006801:Humans; D018928:Immunity, Mucosal; D007371:Interferon-gamma / Q000096:biosynthesis; D000072179:Interleukin-1 Receptor-Like 1 Protein; D007378:Interleukins / Q000096:biosynthesis; D008168:Lung / Q000276:immunology*; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D051379:Mice; D008807:Mice, Inbred BALB C; D011506:Proteins / Q000276:immunology / Q000502:physiology*; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1 / Q000276:immunology / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology; D014162:Transfection
D000485:Allergens; D000911:Antibodies, Monoclonal; C079241:IL1RL1 protein, human; C486189:Il1rl1 protein, mouse; D000072179:Interleukin-1 Receptor-Like 1 Protein; D007378:Interleukins; D008565:Membrane Proteins; D011506:Proteins; D011956:Receptors, Cell Surface; D018123:Receptors, Interleukin; D017472:Receptors, Interleukin-1; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma