Human epidermal Langerhans cells induce tolerance and hamper T cell function upon tick-borne pathogen transmission.

Arthropods are ancient vectors of infectious disease that alter the immune environment of the skin during feeding. The epidermis and its immune sentinels, including Langerhans cells, are critical for protection against ectoparasitic arthropods such as ticks. Here, we investigate how human Langerhans cells respond to clinical and experimental tick bites and concomitant infection with the tick-borne bacterium Borrelia burgdorferi. Using imaging, migration assays, immune spheroid models, and single-cell transcriptomic analysis of patient samples, we show that tick bites and tick saliva reprogram Langerhans cells to increase migration into lymphatic tissues, adopt a tolerogenic state marked by specific transcriptional programs, reduced ability to induce pro-inflammatory helper T cells, and enhanced promotion of type 2 and regulatory T cell responses. This shift dampens protective immunity and helps explain how ticks and their pathogens evade host defense and achieve efficient transmission.