The T cell pathway is one of the two main branches of the adaptive immune system and is responsible for the detection and destruction of altered host cells or foreign bodies. In particular, CD8+ cytotoxic T cells are responsible for the release of molecules such as granzymes and perforins that induce apoptosis and lysis of the targeted cell. In diseases such as cancer, however, upregulation of the protein receptor CTLA4 on CD8+ T cells or of the transmembrane protein PD-L1 on many different types of tumor cells lead to inhibition of CD8+ T cell function and their ability to kill cancer cells. Knowing this, one way in which cancer may be treated could be via drugs that stimulate CD8+ T cells so that they may overcome such inhibitory signals. Molecules that stimulate and enhance T cell function – such as cytokines, small proteins that modulate the immune response - are already present in the human body. A cytokine known as Interleukin-1 (IL-1), for example, has been shown to have the ability to significantly increase the proliferation and activity of CD8+ T cells. Therefore, looking at molecules such as IL-1 as potential therapeutic agents against cancer could be very beneficial. The issue with cytokines, including IL1, however, is that their receptors are often present on many different cell types which causes a problem of side effect toxicity if someone is treated with too high a dose. To address this problem and achieve target cell selectivity, attenuated versions of IL-1ꞵ immunocytokines, termed Activity-on-target-cytokines (AcTakines), have been developed that are inactive towards the IL-1 receptor (IL-1R) until first bound to a target-specific cell surface antigen, such as CD8 on cytotoxic T cells (Fig 1). In this study we sought to determine if it is similarly possible to generate conditionally active, targeted IL-1ɑ immunocytokines with selective activity for CD8+ target cells. IL1a and IL1b both bind to the IL1R but diverge in primary sequence, expression profile and some functional activities. Our findings indicate that two IL-1ɑ AcTakines, constructs 1 and 2, met these criteria, with construct 1 being especially successful as there was little to no IL1R signaling activity in cells that do not express CD8 but activity equal to or higher than that of wild-type IL-1ɑ in cells that do express CD8.