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IL-12p40 heterodimerizes with IL-12p19 and IL-12p35 to produce IL-23 and IL-12, respectively. The functions of IL-12 and IL-23 are best described in T cells in which IL-12 is a potent inducer of Th1 differentiation, whereas IL-23 can amplify Th17 responses in inflammatory diseases. Here we present evidence that mouse IL-12p40 can form a third heterodimer with CD5Like (CD5L). The formation of this new heterodimer, CD5L:p40, is dependent on charged residues and can be induced in myeloid cells under inflammatory conditions such as experimental models of colitis, autoimmune inflammation of the central nervous system, and airway inflammation. We demonstrate that recombinant CD5L:p40 can induce a unique transcriptome and IL-13 expression from effector Th17 cells in a dual-specificity phosphatase 2-dependent manner. We developed a monoclonal antibody that specifically targets CD5L:p40 but not its individual subunits and demonstrate that this blocking antibody exhibits efficacy in reducing an antigen-dependent Th2 response and airway inflammation.