ROLE OF IL-15, IL-2, AND THEIR RECEPTORS IN THE DEVELOPMENT OF T-CELLALVEOLITIS IN PULMONARY SARCOIDOSIS

Recent data suggest that the newly discovered cytokine IL-15 cooperate s with IL-2 in driving T cell-mediated immune responses. The aim of th is study was to determine the role of IL-15 in the regulatory networks leading to the development of T cell alveolitis in the lung of patien ts with sarcoidosis. We demonstrated that alveolar macrophages (AMs) i solated from the bronchoalveolar ravage of patients with active sarcoi dosis expressed IL-15 mRNA and membrane and cytoplasmic IL-15, while A Ms from healthy subjects and patients with inactive sarcoidosis did no t. Pulmonary CD4(+) T cells from sarcoid patients were equipped with t he IL-2R subunits, which are able to bind IL-15, i.e., the IL-2R beta/ IL-2R gamma complex, and proliferated in response to IL-15. Interestin gly, the T cell proliferation elicited by IL-15 was comparable with th at determined by IL-2. Following the addition of graded amounts of IL- 15, IL-2-pulsed T cells showed a significant increase in their stimula tion. TNF-alpha up-regulated the IL-15-mediated proliferative response of bronchoalveolar lavage T lymphocytes. Following the block of the I L-2R beta- and gamma-chains with specific mAbs, the stimulatory activi ty of IL-15 was abolished. The evaluation of the IL-2R on sarcoid AMs demonstrated the constitutive expression of alpha- and gamma-chain mRN A and proteins. Taken together, these findings demonstrate that IL-15 triggers the growth of sarcoid T cells through the IL-2R beta/IL-2R ga mma complex and raise the possibility that AMs may deliver proliferati ve signals for the development of the T cell alveolitis. Modulation of IL-2R on AMs could represent a critical variable in regulating local inflammatory responses.