The subunits of IL-12, originating from two distinct cells, can functionally synergize to protect against pathogen dissemination in vivo

Abstract

Abstract Cytokines are typically single gene products that potently modify immune responses. The IL-12 family is an exception to this paradigm as these cytokines are heterodimers. In the case of IL-12, the subunits, IL-12p40 and IL-12p35 are encoded by two unlinked genes. However, it is canonical that activated myeloid cells co-express both these subunits simultaneously and secrete a fully active heterodimer of IL-12 which then drives IFNγ production by innate and adaptive cells. Using a chimeric mouse model, we identified a novel method of formation for generating functional IL-12 activity in vivo involving IL-12p40 monomers originating from hematopoietic cells which extracellularly associate with IL-12p35 from other non-hematopoietic cells. In the context of a parasitic challenge, we found that this two-cell mechanism of IL-12 formation was sufficient to drive T cell differentiation in local sites, distal to the initial infection, and thereby regulate systemic dissemination of the pathogen. Accordingly, we identify a new collaboration between hematopoietic and non-hematopoietic cells to produce functional IL-12 through the regulated release of individual subunits as a systemic alert system to prepare host tissues for potential pathogen arrival.