The interaction of ticks with their hosts results in a series of complex interactions that balance the defense mechanisms of the host with the countermeasures developed by the tick during evolution. Thus, two conflicting strategies result both in the generation of innate and acquired immune responses against antigens exposed to the host and the development of stratagems to inhibit the responses associated with resistance to a successful feeding process. Among the several products secreted into the mammalian host by feeding ticks, we have cloned a 15 kDa secreted component (Salp15) from Ixodes scapularis that is able to inhibit the activation of CD4+ T cells both in vivo and in vitro. Salp15 inhibits CD4+ T cell activation by the repression of TCR-mediated calcium signals that results in diminished IL-2 production and CD4+ T cell proliferation. The consequence is the generation of defective CD4+ T cell responses both in vitro and in vivo. We hypothesize that Salp15 is an antigen delivered by tick saliva to the mammalian host that is involved in the evasion of immune responses to tick components (Tick immunity). Salp15 binds to specific receptors on the surface of CD4+ T cells resulting in the inhibition of T cell receptor-mediated signals. We propose to 1) Assess early signaling events during CD4+ T cell activation that are affected by Salp15, and 2) Identify and characterize the specific receptor of Salp15 on the surface of CD4+ T cells. These studies will provide a mechanistic explanation of Salp15 activity, and the basis for tick-induced immuno-modulatory actions on several animal species, including mice and humans.