IL-16 has been described as a natural soluble CD4-ligand with immunosuppressive effects in vitro. However, little is known about the effect of IL-16 on immune responses in vivo.In the present study, we examined the effect of IL-16 administration in a murine model of allergic asthma. Next, we determined whether these effects were mediated by modulation of CD4+ T lymphocytes.Intraperitoneal administration of IL-16 completely inhibits antigen-induced airway hyper-responsiveness and largely decreases the number of eosinophils in bronchoalveolar lavage fluid (90%) and airway tissue of ovalbumin-sensitized and challenged mice. Firstly, it appears that thoracic lymph node cells isolated from in vivo IL-16-treated ovalbumin-challenged animals produce less IL-4 (77%) and IL-5 (85%) upon antigenic re-stimulation, when compared to vehicle-treated mice. Secondly, pre-incubation of lymphocytes with IL-16 in vitro reduces antigen-induced proliferation (55%) and Th2-type cytokine production (IL-4; 56%, IL-5; 77%). Thirdly, the presence of IL-16 during priming cultures of TCR transgenic T cells (DO11.10), reduces IL-4 (33%) and IL-5 (35%), but not IL-10 and IFNgamma levels upon re-stimulation.It can be concluded that IL-16 has potent immunosuppressive effects on a Th2dominated allergic airway response.