Paired immunoglobulin-like receptor A is an intrinsic, self-limiting suppressor of IL-5-induced eosinophil development

Eosinophilia is a hallmark characteristic of T(H)2-associated diseases and is critically regulated by the central eosinophil growth factor interleukin 5 (IL-5). Here we demonstrate that IL-5 activity in eosinophils was regulated by paired immunoglobulin-like receptor (PIR)-A and PIR-B. Upon self-recognition of β(2)M molecules, PIR-B served as a permissive checkpoint for IL-5-induced eosinophil development by suppressing the pro-apoptotic activities of PIR-A, which were mediated by the Grb2-Erk-Bim pathway. PIR-B-deficient bone marrow (BM) eosinophils underwent compartmentalized apoptosis, resulting in decreased blood eosinophilia in naïve, IL-5- and aeroallergen-challenged mice. Subsequently, Pirb(−/−) mice displayed impaired aeroallergen-induced lung eosinophilia and induction of lung T(H)2 responses. Collectively, these data uncovers an intrinsic, self-limiting pathway regulating IL-5-induced eosinophil expansion, which has broad implications for eosinophil-associated diseases.