T1/ST2 expression on Th2 cells negatively regulates allergic pulmonary inflammation

The transmembrane form of T1/ST2 (ST2) is a specific marker on murine Th2 cells that have been generated in vitro, or isolated from sites of allergic type 2 inflammation. Despite the association of ST2 with Th2 cells, to date no obligate role for ST2 in type 2 responses in vivo has been described. We have specifically addressed the role of ST2 on T cells by generation of ST2(-/-) mice crossed with ovalbumin (OVA) T cell receptor-transgenic mice. OVA-specific ST2(-/-) cells had normal cytokine responses to T cell activation after in vitro Th2 differentiation, but OVA stimulation of IL-5 was increased. Transfer of OVA-specific ST2(-/-) Th2 cells into BALB/c mice caused exacerbated pulmonary inflammation with occluded airways, elevated airway hyper-responsiveness and increased susceptibility to methacholine challenge that was associated with mortalities of recipient mice. The increased pulmonary inflammation in OVA-specific ST2-/- Th2 cell recipients was associated with selective differences in pulmonary levels of Th2 cytokines compared with OVA-specific ST2(+) Th2 cell recipients. Recipients of OVA-specific ST2-/- Th2 cells had a significant increase in eosinophils and a significant reduction in F4/80(hi) macrophages in the lungs. This is the first demonstration of a role for ST2 expression on Th2 cells down-regulating pulmonary inflammation. These data have major implications for the targeting of ST2 as a therapy for allergic airway disorders.