A novel heterodimer composed of IL-12p40 and CD5L promotes a unique cytokine profile from T cells

Abstract

Abstract The IL-12 family of cytokines (IL-12, IL-23, IL-27, and IL-35) are heterodimers composed of α and β subunits. Both IL-12 and IL-23 utilize IL-12p40 (p40) as their β subunit yet exert distinct proinflammatory outcomes on the T cell response. Upon immune stimulation, the p40 monomer is also secreted from innate immune cells without its binding partners p35 and p19. In order to examine if p40 functions by interacting with additional partners, we generated a library of p40 binders using immunoprecipitation and mass spectrometry. Of the 19 potential binding partners identified biochemically, CD5L, a protein characterized for its role in regulating macrophages was the top hit. We generated a panel of dimer-specific monoclonal antibodies recognizing the p40-CD5L heterodimer. Using this reagent, we found that p40CD5L was present in the serum of both C57BL/6 and BALB/c mice at baseline and increased in the BAL of mice after allergic sensitization. Adoptive transfer and restimulation of transgenic T cells with recombinant p40CD5L resulted in significantly increased production of IL-4 and IL-10 – a unique cytokine profile that has not been identified with other p40-containing cytokines. From these results, we suggest that p40CD5L may function as a novel innate heterodimeric cytokine potentially promoting IL-4 and IL-10 responses. Supported by grants from NIH (R21AI166330-02)