Dengue infection elicits skin tissue-resident and circulating CD8 ⁺ T-cells associated with protection from hospitalization

Dengue is spreading globally and there is urgent need to define immune correlates of protection against this disease. Immune responses against dengue viruses have been studied in blood samples of dengue patients. However, dengue virus infection first occurs in the skin following the bite of an infected Aedes mosquito, and immune responses are initiated within this site. In this study, we investigated the phenotypic, functional and transcriptional profiles of skin and blood T-cell responses and their role in immunity in 73 dengue patients and 10 healthy volunteers. We show that the skin T-cell compartment undergoes dramatic reshaping compared to the blood of dengue patients. CD4 ⁺ and CD8 ⁺ T-cell responses were highly enriched in the skin compared to the blood of the same patients, and skin-based T-cells expressed markers associated with tissue-resident T (T _RM ) cells. While the magnitude of the CD4 ⁺ T-cell response in the skin was independent to that in the blood, CD8 ⁺ T-cell responses in skin and blood were positively correlated. Activated CD8 ⁺ T-cells in the skin expressed a core transcriptional signature of T _RM cells, further supporting their differentiation to the T _RM lineage during infection. The magnitude of both skin and blood CD8 ⁺ T-cell responses was associated with protection from hospitalization in this cohort. These data collectively support a protective role of skin-resident and circulating CD8 ⁺ T-cells in dengue and provide insights into the biology of T _RM cells in human infection. Our findings warrant evaluation of vaccination strategies that induce T _RM cells in the skin to enhance protection against dengue.