IL-22 and TNF-α represent a key cytokine combination for epidermal integrity during infection with Candida albicans

T cells exercise their full impact on target cells through a combination of secreted cytokines. The recently described T helper cell subset Th22 is characterized by a combinatorial secretion of IL-22 and TNF-alpha. Here, we demonstrate that IL-22 increases the TNF-alpha-dependent induction and secretion of several immune-modulatory molecules such as initial complement factors C1r and C1s, antimicrobial peptides S100A7 and HBD-2 (human beta defensin 2), and antimicrobial chemokines CXCL-9/-10/-11 in primary human keratinocytes. The synergism of IL-22 and TNF-alpha is transmitted intracellularly by MAP kinases and downstream by transcription factors of the AP-1 family. The induction of innate immunity is relevant in an in vitro infection model, where keratinocytes stimulated with Th22 supernatants or recombinant IL-22 plus TNF-alpha effectively inhibit the growth of Candida albicans and maintain survival of epithelia. Accordingly, the combinatorial stimulation of keratinocytes with IL-22 and TNF-alpha most efficiently conserves the integrity of the epidermal barrier in a three-dimensional skin infection model as compared with IFN-gamma, IL-17, IL-22 or TNF-alpha alone. In summary, we demonstrate that IL-22 and TNF-alpha represent a potent, synergistic cytokine combination for cutaneous immunity.