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 F4/80hi 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.