Human Macrophages Encode Stimulus-Specific Information of Prior Exposures Through Trained Immunity

Trained immunity (a form of innate immune memory), defined in part by heightened responses to pathogen restimulation, can be generated by many different stimuli. However, both the quantitative differences in trained states generated by different stimuli and the downstream consequences of those differences remain unclear. Here, we used primary human monocyte-derived macrophages to demonstrate phenotypic and molecular stimulus specificity of trained immunity six days after initial exposure. Quantification of cytokine production with single-molecule RNA imaging demonstrated stimulus-specific patterns of response to restimulation, with trained cells showed stronger responses to secondary stimuli more similar to their initial stimulation. Differential licensing of inflammatory transcription factors was associated with encoding of specificities in chromatin six days after training, while memory of some, but not all, training stimuli is lost by eleven days post-training in vitro. Overall, our findings demonstrate that different training stimuli can impart specific memories which generate distinct training phenotypes.