NTRODUCTIONIn this review we summarize our studies on macrophage activation in mice with the scid mutation. Such mice exhibit, to a remarkable extent, a cellular system capable of activating macrophages. This pathway of macrophage activation defmes the cellular immune system operating presumably in its most primitive form without the modulation of B or T cells, i.e., without adaptive immunity. This T cell-independent mechanism of macrophage activation constitutes an important line of defense and protection against certain microbes in scid mice. It is likely that the T cell-independent pathway is also part of the normal response of mice with an intact immune system. Because it is not masked by the T-cell response, the JctV/mouse is an excellent model to defme the cellular and chemical components of the T cell-independent pathway. To date, we have defmed two cell types operating in this system, namely macrophages and natural killer (NK) cells, and three cytokines, interferon-y (IFNy), tumor necrosis factor (TNF) and interleukin-1 (IL-1). Our review summarizes our published results plus those of studies now in press or submitted (Bancroft et