While the molecular basis underlying Th1 and Th2 differentiation still remains to be fully elucidated, recent work has demonstrated that during the commitment of naive cells to either pathway, distinct molecular events occur that result in differential gene expression. In this respect, the transcription factors c-maf 1
and GATA-3 23
have recently been shown to be induced in Th2 cells and demonstrated to play an important role in Th2 cytokine secretion. Moreover, GATA-3 not only appears to directly regulate Th2 phenotype differentiation, but also functions to inhibit commitment to the Th1 phenotype by inhibiting IFN-γ secretion and the acquisition of the β2 subunit of the IL-12 receptor 4
. However, overexpression of GATA-3 in differentiated effector populations has minimal effects on IL-4 or IFN-γ secretion 4
, suggesting that other as yet unidentified factors regulate Th2 cytokine production from effector cells.
More recently, several transmembrane receptors have been shown to be differentially expressed on Th subsets. The CC chemokine receptors (CCR)1
CCR3 and CCR4 are expressed on Th2 cells, whereas CCR1 and CCR5 are expressed on Th1 effector populations 56
, providing an attractive mechanism by which Th subsets are preferentially recruited to distinct inflammatory sites. In addition to chemokine receptors, two members of the IL-1 receptor superfamily, IL-1Rrp (7
; subsequently identified as the IL-18 receptor 8
) and T1/ST2 9
, have also been shown to be differentially expressed on Th cells. The IL-18 receptor is expressed on activated Th1 cells and regulates IFN-γ secretion, IL-12R β2 expression, and Th1-mediated inflammation in vivo 10
. T1/ST2, originally identified as a gene induced by serum stimulation of fibroblasts 9
, has more recently been demonstrated to be overexpressed on Th2 effector cells 1112
although its function still remains unclear.
In this report, we provide evidence to suggest that T1/ST2 is more than a stable marker on the surface of Th2 cells, and demonstrate that T1/ST2 is a crucial cell surface receptor that is required for Th2 effector responses. These data suggest that T1/ST2, like other members of the IL-1 receptor superfamily including human Toll (hToll, Toll-like receptor [TLR]-4), TLR-2, and the IL-18 receptor, are critical regulators of both innate and adaptive immunity 10131415