Summary: An IL-12 family heterodimer that regulates IL-4 production by T cells The immune system tailors effector responses to match both specific pathogens as well as the tissues they infect. In this context, a pair of cytokines (IL-12 and IL-23) produced by innate cells early in an infection play an important role. IL-12 drives the differentiation of T cells towards IFNγ producing effectors while IL-23 promotes IL-17 responses. Both IL-12 and IL-23 are heterodimers which share a common subunit (IL-12p40) but differ in the 2nd subunit (IL-12p35 for IL-12 and IL- 23p19 for IL-23). The significance of this proposal is that we identify a new innate cytokine in this family, which promotes the differentiation of IL-4 and IL-10 producing T cells. This new heterodimeric cytokine also uses the IL-12p40 subunit, but binds a distinct partner from the other proteins, a secreted CD5-like antigen called CD5L. In this proposal, we will examine the mechanisms by which P40+CD5L exerts its IL-4/IL-10 promoting activity, using new recombinant proteins, specifically developed monoclonal antibodies and available knockout mice. Accordingly, the following specific aims will evaluate our central hypothesis that “A heterodimer formed by IL-12p40 plus CD5L functions as an innate cytokine and amplifies IL-4 and IL-10 production by lymphocytes in vivo”. In specific aim 1 we characterize the different lineages of immune cells (including T, B, NKT, ILCs, macrophages, etc.) which respond to P40+CD5L in vivo. We will then evaluate the cellular receptors involved in sensing P40+CD5L and the major signaling pathways downstream of these receptors in activated T cells. Finally, we will perform unbiased transcriptomic analysis to identify the global impact of P40+CD5L. In the second aim, we will use infection and tumor models, exploiting natural variation of P40+CD5L levels in different mouse strains to pinpoint its role in two contexts where the IL4 and IL10 play critical roles. On completion, of these studies we expect the report of a new innate cytokine to be of interest to the broader community as well as the development of new immunotherapies using the reagents we have developed. Future studies will also help incorporate the biology of P40-CD5L into the network of other IL-12 family cytokines and develop a more complete understanding of innate- adaptive communication in the immune system.