Interleukin-16 Stimulation Results in Recruitment and Potential Induction of De Novo FoxP3+ Treg Cells in the Lungs

摘要

As a natural ligand for CD4, IL-16 has been shown to preferentially induce migration in Thl cells, and in long-term cultures with IL-2, IL-16 facilitates expansion of CD4+CD25+ cells. In addition, IL-16 has an immunomodulatory role in asthmatic inflammation, as exogenous administration significantly reduces inflammation and airway hyperreactivity. The mechanism for this, however, is not clear. Based on its functional characteristics and potential immunomodulatory role, we investigated the ability of IL-16 to recruit and influence development of T regulatory (Treg) cells. We now demonstrate that IL-16 preferentially induces migration in a CD25+, CTLA-4+ human T cell subset and that responding cells produce IFN-7 and TGF-p, but no IL-10. These cells are relatively unresponsive to antigenic stimulation and can suppress proliferation and IL-5, but not IFN-7, production by autologous T cells. We further demonstrate that IL-16 instillation into Balb/c mice results in a preferential lung recruitment of cells that are Foxp3+. In addition, we show that IL-16 stimulation may facilitate de novo induction of Foxp3+ Treg cells, as stimulation of FoxP3-negative T cells for 48 hours results in expression of FoxP3 mRNA and protein, and further, IL-16 stimulation of Jurkat cells expressing the FoxP3 promoter results in a 15-20-fold induction of promoter activity. These data indicate that at sites of inflammation IL-16 may contribute to selective Treg cell expansion through the preferential induction of a migratory response from existing Treg cells, as well as by the induction of de novo generation of FoxP3+ cells. These findings offer a potential mechanism for the immunosuppressive effects of IL-16 seen in asthma.